View More View Less
  • 1 Instituto Venezolano de Investigaciones Científicas (IVIC-Zulia), Nephrology Service Hospital Universitario, Universidad del Zulia, Venezuela
  • 2 University of Colorado Anschutz Medical Campus, USA
Open access

The development of stress drives a host of biological responses that include the overproduction of a family of proteins named heat shock proteins (HSPs), because they were initially studied after heat exposure. HSPs are evolutionarily preserved proteins with a high degree of interspecies homology. HSPs are intracellular proteins that also have extracellular expression. The primary role of HSPs is to protect cell function by preventing irreversible protein damage and facilitating molecular traffic through intracellular pathways. However, in addition to their chaperone role, HSPs are immunodominant molecules that stimulate natural as well as disease-related immune reactivity. The latter may be a consequence of molecular mimicry, generating cross-reactivity between human HSPs and the HSPs of infectious agents. Autoimmune reactivity driven by HSPs could also be the result of enhancement of the immune response to peptides generated during cellular injury and of their role in the delivery of peptides to the major histocompatibility complex in antigen-presenting cells. In humans, HSPs have been found to participate in the pathogenesis of a large number of diseases. This review is focused on the role of HSPs in atherosclerosis and essential hypertension.

Abstract

The development of stress drives a host of biological responses that include the overproduction of a family of proteins named heat shock proteins (HSPs), because they were initially studied after heat exposure. HSPs are evolutionarily preserved proteins with a high degree of interspecies homology. HSPs are intracellular proteins that also have extracellular expression. The primary role of HSPs is to protect cell function by preventing irreversible protein damage and facilitating molecular traffic through intracellular pathways. However, in addition to their chaperone role, HSPs are immunodominant molecules that stimulate natural as well as disease-related immune reactivity. The latter may be a consequence of molecular mimicry, generating cross-reactivity between human HSPs and the HSPs of infectious agents. Autoimmune reactivity driven by HSPs could also be the result of enhancement of the immune response to peptides generated during cellular injury and of their role in the delivery of peptides to the major histocompatibility complex in antigen-presenting cells. In humans, HSPs have been found to participate in the pathogenesis of a large number of diseases. This review is focused on the role of HSPs in atherosclerosis and essential hypertension.

Biology of Heat Shock Proteins (HSPs)

In 1962, Feruccio Ritossa (94) described puffiness in Drosophila salivary chromosomes and changes in gene expression in response to heat. This serendipitous finding was followed 12 years later by the identification of the proteins overproduced by the increase in temperature that were named HSPs (113). Subsequent studies demonstrated that the upregulation of HSP was not restricted to hyperthermia but was also induced by hypoxia, ischemia-reperfusion, energy depletion, physical stretching, acidosis, generation of reactive oxygen radicals, and in fact by just about every condition generating cellular stress (55). At present, more than 60,000 references on HSP are listed in PubMed archives.

The HSPs represent one of the most ancient and conserved proteins in prokaryotic and eukaryotic cells. They have a high interspecies homology and are constitutionally expressed in most cells. Their overexpression during stress has been demonstrated in every species that has been investigated, including aquatic corals, desert ants, plants, bacteria, and mammals. The HSP response to stress is so universal that it has been used as a non-specific bioindicator of pollutant contamination of the environment (116).

The transcription of the HSP gene is mediated by the interaction of heat shock elements in the gene promoter regions with the activated (phosphorylated) trimers of heat shock factors (HSFs). These HSFs are normally present in the cytoplasm as inactive monomers and when activated translocate to the nucleus. The hyperphosphorylation of inactive HSFs is induced by stressful conditions in a ras-dependent manner by mitogen-activated protein kinases. The family of HSFs independently or in concert regulates HSP activity driving or repressing gene activation and transcription. The human genome encodes six HSF proteins. In vertebrates, HSF1 and HSF2 are the most widely expressed HSFs. HSF1 plays the central role in the response to stress and cell survival. In contrast, HSF2 is inactivated by hyperthermia and sequestered in the cytoplasm thus avoiding interaction with the HSF1 transferred to the nucleus and may function as cancer suppressor (31).

HSPs are cytoprotective by acting as chaperones in the folding, intracellular transport, and repair of degraded proteins. In their chaperone functions, HSPs promiscuously interact with peptides (“clients”) and dissociate from them once their goal is completed. The upregulation of HSPs is activated and inactivated by a fine-tuned network of transcriptional and post-transcriptional pathways and by interaction with co-chaperones that can bind simultaneously and are integrated in the management of the client peptide (31, 105).

HSPs constitute 5%–10% of the total protein content of the cells under physiological conditions and may increase up to 15% under stress (74). They are distributed in the cytoplasm, nucleus, endoplasmic reticulum, and mitochondria and because of the large number of their client molecules, the function of HSPs is not restricted to situations of cellular stress. They are critical participants in cellular homeostasis and signal transduction. In the immune response, they are involved in preservation and intracellular trafficking of antigenic peptides to the major histocompatibility complex (MHC), expression of toll-like receptors (TLRs), adhesion molecules, and production of pro-inflammatory cytokines (4, 28, 54, 81, 83, 90, 92, 105, 115). While the results of many studies have given support to the roles of HSPs stimulating immunity and inflammation, it is impossible at times to separate the effects of the HSP itself from its association with contaminating agents, in particular, endotoxin originated in the bacteria used for HSP extraction. As will be discussed later, the findings of HSP70-induced production of cytokines and its binding to the MHC in antigen-presenting cells (APCs) are abrogated when endotoxin-free HSPs are used (9, 29).

HSPs are classified by their molecular weight and are grouped in families (45, 134). The most important HSPs in human diseases are:

  1. Small HSP (sHSP) group. These HSPs have a small size (16–40 kDa) and are present in the cytoplasm and the nucleus. They include HSP27 (HSPB1), heme oxygenase (HSP32), αB-crystallin (HSPB5), and αA-crystallin (HSPB4). sHSPs function as cytoskeleton stabilizers and some have antioxidant properties (HSP32) of central importance in some disease states. sHSPs prevent the irreversible aggregation of damaged proteins in an ATP-independent manner and transfer damaged proteins to ATP-dependent chaperones, for example, HSP70. Members of this family inhibit specific stages of some apoptotic pathways. Numerous studies have uncovered protective role of HSP27 in atherosclerosis.
  2. HSP40. HSP40 is a member of the DnaJ family that comprises the largest number of HSPs in humans. This family presents a J-domain responsible for recruitment of members of the HSPA family (includes HSP70) and stimulation of ATPase activity and thus regulates the activity of other co-chaperones. HSP40 promotes rearrangement of proteins by successive folding and refolding of protein aggregates and facilitates collagen preservation and transport of collagen.
  3. HSP60. This chaperonin family includes HSP60 in mammals and mycobacterial HSP65, chlamydial HSP60, and Escherichia coli GroEL homologues. HSP60 is present in the cytoplasm, mitochondria, endoplasmic reticulum, and nucleus. HSP60 binds to partially folded polypeptides, prevents their aggregation, and assists the development of correct refolding. HSP60 is released from cells after necrosis and is an important signal of cell death. The role of HSP60 in atherosclerosis, rheumatoid arthritis, diabetes mellitus, and neurological diseases has extensively been studied.
  4. HSP70. HSP70 and other members of the HSPA family have an N-terminal ATPase domain and a C-terminal domain that bind hydrophobic regions in polypeptides and by repeated folding and refolding avoids the exposure and aggregation of polypeptide clients. The chaperone function of HSP70 involves the participation of co-chaperones and is involved in a multitude of protein interactions. HSP70 family members may facilitate DNA repair and play a role in the transfer of the client peptides across membranes. HSP70 has been implicated in the pathogenesis of atherosclerosis and as an autoantigen in the pathogenesis of hypertension.
  5. HSP90. HSP90 is a member of the HSPC family. It has an ATP-binding amino terminal domain, a middle domain for binding with clients and a carboxyterminal domain, responsible for dimerization and interaction with co-chaperones. Humans have two HSP90 genes: HSPα that is constitutively expressed and HSPβ that is heat-induced (105). HSP90 recognizes and binds denatured proteins preventing irreversible aggregation and cooperates with members of the HSPA family facilitating nucleotide exchange. In addition, HSP90 binds to specific glucocorticoid receptors. Deletion of HSP90 allows the expression of normally suppressed phenotypes, which raises the possibility of HSP90 could play a role in suppressing detrimental spontaneous mutations (43, 102). It plays a role in the pathogenesis of atherosclerosis and systemic lupus erythematosus.

Characteristics of HSPs relevant to autoimmune disease

While HSPs are primarily cytoprotective as described earlier, they are immunodominant molecules with several characteristics that may stimulate autoimmune reactivity. One of these characteristics is the highly preserved interspecies homology. The similarity of HSPs across species carries the potential of cross-immune reactivity between the HSPs in invading microorganisms and the corresponding HSPs in the host and thereby may cause unintentional autoimmune responses directed to human HSPs. A number of investigations have made use of the homologies between human HSP60 and E. coli GroEL, Mycobacterium tuberculosis HSP65, Chlamydia trachomatis HSP60 GroEL-like and HSP60 of Candida, Aspergillus, and Histoplasma (47, 69, 104, 108, 117, 128). Similar homologies between human HSP70 and the HSP70 in M. tuberculosis and Mycobacterium leprae, Candida, Aspergillus, and Histoplasma, and DnaK-like HSP70 of C. trachomatis have been the bases of important investigations (42, 69, 104, 107, 119, 125). In fact, molecular mimicry is used in the design of therapeutic strategies that induce regulatory T cell (Treg) responses in the host by administration of specific peptide sequences of bacterial HSPs (120).

In addition to molecular mimicry, it has been postulated that HSPs can stimulate immunity against peptides generated during cellular injury because of their capacity to enhance immune reactivity directed to other antigens. This characteristic is the reason to incorporate HSP to vaccines directed against specific cancers (17). Finally, HSPs have also been assigned a critical role in facilitating the traffic of extracellular and intracellular peptides to MHC types I and II in APCs by canonical and cross-presentation pathways (39, 40, 138). However, some studies have questioned the direct stimulatory effects of HSPs on immune reactivity to other peptides. Careful studies have demonstrated that HSP70 contamination with endotoxin is responsible for the generation of tumor necrosis factor from macrophages (29) and endotoxin contamination is also responsible for HSP70 activation of APCs (9). Furthermore, it has been reported that the immunostimulatory properties of HSP70-antigen fusions are lost after endotoxin depletion (66). Therefore, some pro-inflammatory and immune stimulatory functions of HSPs may require the association with other components; in fact, HSP vaccines prepared with therapeutic purposes are prepared in association with other peptides (32, 50).

In addition to the role of HSPs in stimulating autoimmunity in disease conditions, HSPs are emerging as a central player in natural autoimmunity. Antibodies against HSPs, particularly HSP60, are detected in the umbilical cord blood, maintain long-term stable levels, and are independent of infection (121). Therefore, natural autoantibodies of HSPs are part of a normal immune system (72, 118). The role of natural autoantibodies is a subject of debate and it has been proposed that they have a protective function. Disease-related HSP immune reactivity would result from changes in phenotypes of natural autoantibodies or by increase above a certain threshold as a consequence of environmental (repeated infections) or genetic factors (20).

Another aspect relevant to the autoantigenic potential of HSPs is their possible extracellular localization. Although HSPs are intracellular proteins, their extracellular location is critical for their capacity to trigger HSP-directed autoimmune reactivity. HSPs or HSP-protein complexes may escape to extracellular locations by passive leakage during necrosis as well as by several mechanisms unrelated to cell damage. HSPs may be engulfed inside cell membranes and released in ectosomes and exosomes from cells in the peripheral circulation. The ectosomal location of HSPs has been demonstrated for HSP27, HSP70, HSP60, and HSP90 (8, 16, 34, 57). In addition, HSPs may be extruded from the cells in association with lysosomes. In support of this mechanism is the finding that HSP70 has been identified in association with lysosomal proteins (65). Finally, it is possible but presently unproven that direct protein translocation of HSPs may take place through interaction with lipids in cell membranes, as has been shown to occur for fibroblast growth factor-2 (79). In specific circumstances, both passive leakage and active secretion may be responsible for the extracellular presence of HSPs (64). Any of these mechanisms may be responsible for the existence of circulating levels of HSP and anti-HSP70 in normal individuals (84, 86, 110).

In humans, the role of HSP has been studied in a large number of unrelated conditions and diseases, including aging, cancer, transplantation, atherosclerosis, hypertension, Alzheimer’s disease, diabetes, arthritis, multiple sclerosis, asthma, neurodegeneration (Huntington’s chorea and Parkinson’s disease), cerebral and myocardial ischemia, heat-stress associated nephropathy, and immunity to infectious agents. The present review will focus on the role played by HSP in the pathogenesis of atherosclerosis and essential hypertension.

HSPs and Atherosclerosis

Atherosclerosis is a disease characterized by deposition of lipids, particularly low-density lipoproteins (LDLs) in the intimal layer of large- and medium-sized arteries in association with infiltration of immune cells and remodeling of arterial walls. The lipid composition of the plaques and the infiltration of mononuclear cells were described almost two centuries ago (71), but the important role of inflammation in the pathogenesis of the disease has been recognized only in the past three to four decades (100).

The critical role of immune reactivity in atherosclerosis was originally elucidated by studies that examined the results of treatment with immunosuppressive agents. Using a model of high fat diet-induced atherosclerosis in rabbits, our group (99) and others (33, 123) showed that treatment with the immunosuppressive agent, mycophenolate mofetil, markedly prevented plaque formation, infiltration of inflammatory cells, and the proliferation of vascular smooth muscle cells in the aorta (Fig. 1). Importantly, the reduction of the infiltration of immune cells was also associated with a reduction in the lipid (cholesterol) content in the vessel walls, thereby underlining a role of local inflammation in the formation of the atherosclerotic plaque. The notion that atherosclerosis is an autoimmune disease was advanced by Wick et al. (129) and the knowledge that oxidized LDL is toxic for endothelial cells prompted research on the nature of the immune reactivity induced by oxidized LDL and the proliferation of smooth muscle cells in arterial walls (78). In recent years, significant insight has been gained on the involvement of the innate and adaptive immune reactivity in atherosclerosis and on the role played by HSPs in the pathogenesis of the disease (129).

Fig. 1.
Fig. 1.

Effect of immune suppression with mycophenolate mofetil (MMF, 30 mg/kg daily) on atherosclerosis induced in rabbits by the ingestion of 1% cholesterol diet (CHO) for 12 weeks. (A) No difference was detected in the plasma cholesterol between the CHO and CHO + MMF groups (n = 10 in each group). However, there was a reduction of more than 50% atherosclerosis in the aorta (B and C) and an eightfold reduction in macrophage infiltration (D). Abdominal aortic in CHO group (E) shows extensive atherosclerosis plaques that were not present in the CHO + MMF groups (F). Figure made using data from (99). **p < 0.01. ***p < 0.001

Citation: Physiology International Acta Physiol Hung 105, 1; 10.1556/2060.105.2018.1.4

The atherosclerosis lesion

The initial lesions in atherosclerosis are fatty streaks in the intima (Fig. 2). Oxidized LDLs (oxLDL) act as danger-associated molecular patterns (DAMPs) that stimulate innate immunity, generating autoantigens that engage the adaptive immune response. Local inflammation is modulated by participation of Treg responses (111). Even in the early stages of fatty deposition, there is a cellular component in the lesion, consisting of foam cells, macrophages, and T cells. B lymphocytes are more prominent in the adventitial layer of the arteries. The lesion evolves to the formation of plaques that may be stable and covered by a fibrous cap. Growth and rupture of the plaque and remodeling of the arterial wall result from active inflammation driven by the production of pro-inflammatory cytokines and prothrombotic mediators.

Fig. 2.
Fig. 2.

The role of HSP in the pathogenesis of atherosclerosis. Available evidence suggests that overexpression of HSP27 is protective, whereas overexpression of HSP60 is atherogenic. The effects of HSP70 are inconclusive and HSP90 aggravates and complicates atheroma. Conflicting evidence exists in relation to associations between HSP levels and severity of atherosclerosis (Table I). Induction of regulatory T cell responses with HSP60 and derived peptides improves experimental atherosclerosis. The stages of atherosclerosis were modified from images in Dreamsite.com. Numbers in parenthesis indicate the corresponding references

Citation: Physiology International Acta Physiol Hung 105, 1; 10.1556/2060.105.2018.1.4

Table I.

Selected studies that offer insight on the role of HSPs in atherosclerosis

HSPExperimental modelFindingsReferences
HSP27Cell cultureIncreased activation of NFκB macrophages and production of pro- and anti-inflammatory cytokines(103) (Φ)
PatientsLow plasma HSP27 levels associated with coronary artery stenosis(106)
(*) ApoE−/− mice overexpressing HSP27Reduced de novo atherosclerosis and increased plaque stability(106)
Patients (endo-atherectomy and serum samples)Low HSP27 in atherosclerotic plaques and low serum levels in patients with atherosclerosis(68)
ApoE−/−HSP27 (**) miceInverse correlation between lesion area and HSP27 levels. Reduction of IL-1β and increase in IL-10 in mice overexpressing HSP27(91)
ApoE−/−HSP27 (**) miceChronic overexpression of HSP27 reduces lesions and arterial remodeling(21)
HSP60ApoE−/−miceHSP60 (and HSP70) overexpression precedes inflammation(46)
Review of several experimental modelsAdoptive transfer of T cells reactive to HSP60 induces atherosclerosis. Tolerization with HSP60-derived peptide arrests atherosclerosis(127)
PatientsSerum HSP60 and anti-HSP60 levels correlate with atherosclerosis, anti-lipopolysaccharide, and various markers of inflammation(87, 131, 133, 135)
HSP70PatientsInverse relationship between HSP70 levels and severity of atherosclerosis(68, 141)
PatientsHigh plasma HSP70 levels and anti-HSP70 in peripheral vascular disease(130)
SD ratsElevation of plasma HSP70 precedes diet-induced atherosclerosis(132)
Cell culturesHSP70 bound to plasma membrane activates NFκB and upregulates the expression of pro-inflammatory cytokines by CD4- and Ca-dependent pathways(4) (Φ)
HSP90Atherosclerotic plaques human and miceHSP90 immunostaining was increased in inflammatory regions of plaques, inhibition of HSP90 attenuates inflammation in atheromas(62)

*HSP27 overproduction in the apolipoprotein E −/− (ApoE−/−) atheroprone mice induced by transplantation of bone marrow overexpressing HSP27.

**The apoE−/−HSP27 mice are a cross-bred product of ApoE−/− mice and mice overexpressing HSP27. SD: Sprague–Dawley. Φ indicates studies using recombinant HSP purified and analyzed for potential contamination with endotoxin

The immune system in atherosclerosis

Innate and adaptive immunity triggered by the generation of lipid peroxidation products drives the inflammatory lesion in atherosclerosis (11, 38). The critical role of the innate immune response in the pathogenesis of atherosclerosis has been underlined by the studies of Ridker et al. (93) who showed a reduction in the recurrent cardiovascular-related death, myocardial infarction and stroke, independent of lipid lowering, with the treatment with a monoclonal antibody targeting interleukin (IL)-1β. Strong evidence also supports the participation of adaptive immunity in the progression of atherosclerosis as oxidized lipoproteins generate the production of Th1 cytokines, a process that is suppressed by the Th2 cytokine IL-5 (12).

In human plaques, 70% of T cells are CD4+ T cells and almost all remaining cells are CD8+ T cells (44). Tregs, Th17 cells, and natural killer cells are also present, but in lesser numbers, in atherosclerotic lesions (48, 49). In later stages, tertiary lymphoid organs containing a variety of T-cell types and B cells are formed in the arterial adventitia (76). The role of T-cell subtypes has extensively been studied. CD4+ T cells aggravate atherosclerosis (139, 140). The Th1 subtype of CD4+ T cells is pro-inflammatory and proatherogenic (15, 35), whereas the Th2 subtype has been found both to protect (12) as well as to aggravate (23, 51) atherosclerosis. Tregs are atheroprotective (1). Conflicting reports indicate that IL-17 may attenuate (22, 112) or worsen (26, 30, 109) atherosclerosis. Infiltrating CD8+ cytotoxic T cells favors plaque instability and rupture (56) and natural killer T cells have been found to be proatherogenic in early stages of the disease (5).

The role of B cells in atherosclerosis remains controversial, with some studies indicating protection, whereas others suggesting acceleration of the disease (49).

HSPs in atherosclerosis

The most extensively studied HSPs in atherosclerosis are HSP27, HSP60, HSP70, and HSP90. Specific findings and the experimental models used in several investigations are shown in Table I. The protective and atherogenic potential of overexpression of these HSPs are summarized in Fig. 2.

HSP27

The intracellular chaperone function of HSP27 is regulated by phosphorylation and dephosphorylation in large aggregates that modulate the assembly of an ATP-independent network (6). As a chaperone, HSP27 plays a role in RNA stabilization, supports antioxidant responses, and is antiapoptotic (8). Extracellular release from atherosclerotic tissue may result from cellular injury or occur in association with secretory lysosomes or exosomes. In the extracellular location, HSP27 binds to a number of cell membrane receptors in endothelial cells and immune cells, including CD91, CD40, CD36, CD14, scavenger receptor A (SR-A), and TLRs: including TLR2, TLR3, and TLR4 (11). Recombinant HSP27 induces TLR-mediated activation of NFκB with the secretion of pro-inflammatory as well as the anti-inflammatory (IL-10 cytokines) (103). In atherosclerosis, available evidence supports the notion that HSP27 offers protection against the progression of the disease. In fact, the identification of HSP27 as an estrogen receptor-associated protein is likely the reason for the apparently protective role of estrogens in atherosclerosis (75, 91). Atherosclerotic plaques have lower HSP27 content (67), lower circulating levels of HSP27 are associated with more severe atherosclerotic disease (106), and HSP27 overexpression protects mice from atherosclerosis (21). Potential mechanisms involved in the anti-atherogenic activity of HSP27 include the suppression of NFκB activation by intracellular HSP27 (8) and the possible participation of HSP27 in lipid homeostasis, since it competes with LDL binding to SR-A, attenuates foam cell formation (8), and reduces the cholesterol content in the serum and atherosclerotic plaques (21).

HSP60

Endothelial cells express HSP60 under a variety of stressful conditions. In addition, the cross-reactivity between bacterial and human HSP60 may be responsible for the development of a harmful autoimmune reactivity that may be an undesirable consequence of a preexisting protective immunity to an infectious agent (54, 127, 128). HSP60 has a direct atherogenic potential and the accumulated evidence supports the notion that HSP60-reactive T cells initiate atherosclerosis and the antibodies directed to HSP60 drive the chronicity of the disease (Fig. 2). In human atherosclerosis, several HSP60 epitopes have been found to have T and B cell cross-reactivity with bacterial HSP60 (128). Experimental studies have shown that upregulation of HSP60 expression precedes the development of atherosclerotic lesions (46) and genetically normocholesterolemic mice develop atherosclerotic lesions if immunized with HSP60; furthermore, adoptive transfer of HSP60 reactive T cells induces early (fatty streaks) atherosclerosis (127). In humans, high-circulating levels of HSP60 and anti-HSP60 are correlated with atherosclerotic cardiovascular disease (87, 133, 135), carotid artery wall thickness (131, 133), and atherosclerosis-related morbidity and mortality (136). Specific T-cell immunity to HSP60 exists in the early stages of atherosclerosis (53) and T cells obtained from human atherosclerotic lesions show cross-reactivity with bacterial (mycobacterium and chlamydia) HSP sequences (2).

While contamination with endotoxin was not rigorously excluded in all studies, it has been shown that HSP60 administration could promote or suppress atherosclerosis depending on route of administration, the type of APCs, and the co-stimulatory molecules involved. The parenteral route of HSP60 administration induces adhesion molecules and infiltration of HSP60-specific T cells that are followed by secretion of pro-inflammatory mediators and anti-HSP60 antibodies, invasion of macrophages, lipid deposition, and the formation of atherosclerotic plaques. The oral or nasal route of administration of HSP60 (or HPS60-derived peptide sequences cross-reactive with M. tuberculosis) induces tolerance. Tolerance develops as a consequence of the generation of Tregs and anti-inflammatory mediators (IL-10 and transforming growth factor beta) and results in reduced atherosclerotic lesions (127). The induction of oxLDL-reactive Tregs also reduces plaque formation and when peptide sequences of human apolipoprotein B, human HSP60, and Chlamydophila pneumoniae were used in combination, a synergistic atheroprotection was found (61). As noted by Wick (127), the tolerization strategies are based on the use of peptide sequences with high homology to self that, nevertheless, are immunogenic. Protective vaccines against atherosclerosis using peptides derived from ApoB100, HSP60, and a combination of their epitopes are being actively investigated at present (32).

HSP70

HSP70 is found in the atherosclerotic plaques and is overexpressed in advanced lesions. HSP70 attenuates the activation of NFκB, which would suggest anti-inflammatory activity (134); however, there are conflicting reports that preclude assigning HSP70 a definite role in atherosclerosis at present (Fig. 2). Plasma levels of HSP70 have been found to have an inverse (68, 141) as well as a direct (130, 132) association with the severity of atherosclerosis. HSP70 administration has been found to induce production of IL-6 (pro-inflammatory) (4) as well as Treg (anti-inflammatory) response (125). A high-cholesterol diet has been shown to increase HSP70 plasma levels and exogenous HSP70 induced overexpression of adhesion molecules in peripheral blood mononuclear cells. These results suggest that HSP70 favors infiltration of mononuclear cells and atherosclerosis (132). In contrast, studies investigating the inhibition of HSP90 activity (62) have found that the observed reduction of inflammation and oxidative stress in arterial walls was associated with increased expression of HSP70 and suggested protective effects of HSP70 stimulation. The pro- and anti-atherogenic effects of HSP70 are presently a matter of debate (10).

HSP90

Work on HSP90 has principally centered in cancer. Several studies have explored its role in atherosclerosis, where overexpression of HSP90 is associated with features of plaque instability. Inhibition of HSP90 has resulted in a reduction in inflammation and in oxidative stress resulting from reduced activation of transcription factors (signal transducers and activators of transcription and NFκB) and suppression of pro-inflammatory cytokines. Interestingly, the beneficial effects of suppressing HSP90 activation are associated with overexpression of HSP70 that is assumed to contribute to an overall anti-inflammatory and atheroprotective activity of HSP90 inhibition (62).

HSPs in hypertension

The hypertensive condition

Blood pressure is a biological variable with normal distribution and the definition of hypertension is arbitrary and related to the risk that is attributed to progressively higher values. Hypertension (blood pressure ≥140/90 mmHg) is the most important contributor to the global burden of disease and causes 9.4 million deaths every year; furthermore, the worldwide prevalence of hypertension is predicted to increase 10% between 2000 and 2025 (60). Hypertension is classified as secondary when there is a clear etiologic factor and primary (essential) when a well-defined cause of high blood pressure is not apparent and hereditary and environmental influences play a pathogenic role. More than 65 genetic loci have been found in association with high blood pressure, yet, most of them correspond to genes not usually related to blood pressure homeostasis and the combination of genetic characteristics has been estimated to explain no more than 3% of the hereditability of hypertension (77). Putative causes of essential hypertension include lower birth weight resulting from maternal malnutrition (137) and epigenetic modification of genes (59). The importance of the ambulatory blood pressure determinations, the risks apparently imposed by blood pressure variability, the recommended treatment approaches, and the guidelines for blood pressure control have recently been reviewed (89).

The ability of a high salt diet to increase blood pressure has been recognized for many years (13, 36) and the concept of salt sensitivity refers to an increase in blood pressure resulting from changes in standardized low and high salt administration that exceed “normal” variation (124). Salt sensitivity increases with age and arterial rigidity. While hypertension was classically viewed as strictly a hemodynamic disorder, increasing evidence has showed that hypertension is driven, at least in part, by inflammation in the kidneys (suppressing pressure natriuresis), in the arterial walls (impairing endothelial vasodilatation), and in the central nervous system (stimulating the sympathetic outflow) (96, 97).

Autoimmunity in the pathogenesis of hypertension

The immune cell infiltration in the kidney in salt-sensitive hypertension consists of both T cells and macrophages. Evidence that these cells have a role in hypertension has been shown in experimental models that evaluated the changes in blood pressure resulting from depleting specific cell populations. Using this approach, there is evidence for a prohypertensive role of macrophage infiltration (18, 24, 126), CD4 and CD8 T cells (37, 70, 101, 114), T17 cells (3, 80), and B cells (19), as well as the anti-hypertensive role of Tregs (7, 63, 73).

It has been postulated that the inflammatory response may be initiated by local injury induced by renal vasoconstriction, resulting in ischemia that stimulates release of DAMPs that activate the innate immune response, followed by the exposure of specific endogenous antigens that trigger an adaptive immune response (9597).

In hypertension, HSP70 as well as isoketal-modified proteins may represent endogenous antigens of importance in the pathogenesis of high blood pressure (Fig. 3).

Fig. 3.
Fig. 3.

HSP70 is a relevant endogenous antigen in essential hypertension. Inflammation resulting from innate and adaptive autoimmunity induces and sustains hypertension. Experimental induction of tolerance to HSP70 results in the generation of IL-10-driven regulatory T cell response that prevents inflammation and salt-induced hypertension (88). DAMPs: danger-associated molecular patterns; PAMPs: pathogen-associated molecular patterns; CNS: central nervous system; SNS: sympathetic nervous system; CO: cardiac output; PVR: peripheral vascular resistance

Citation: Physiology International Acta Physiol Hung 105, 1; 10.1556/2060.105.2018.1.4

Isoketal-modified proteins

Studies in several experimental models by David Harrison and co-workers indicate that γ-ketoaldehydes (isolevuglandins or isoketals) resulting from oxidation of lipoproteins bind to lysine residues in proteins and generate protein adducts that represent autoantigens of pathogenic relevance in hypertension. These isoketal-modified proteins have been found to stimulate T-cell activation (52), and to participate in the co-stimulatory process of antigen recognition (122) and in the generation of memory cells (41).

In humans with hypertension, the isoketal-protein adduct content of mononuclear cells, CD14+ cells and CD18+ dendritic cells in peripheral blood is several-fold higher than in normotensive controls and the number of isoketal-positive CD14+ and CD83+ cells correlate with the degree of hypertension (52).

HSP70

Another autoantigen with potential participation in the pathogenesis of hypertension is HSP70 (98). In support of this possibility, we found that renal overabundance of HSP70 (but not other HSPs), circulating anti-HSP70 antibody titers and T-cells reactive to HSP70 were present in several experimental models of hypertension (14, 82, 95). Subsequent studies were conducted in the model of salt-induced hypertension that follows transient inhibition of nitric oxide synthase. In this model, T cells present a clonal CD4 response to HSP70 and the intraperitoneal injection of a highly preserved amino acid sequence of M. tuberculosis HSP70 resulted in the generation of IL-10-producing Tregs and prevention of hypertension. In addition, adoptive transfer of T cells isolated from the spleen of tolerized rats reversed hypertension. Furthermore, HSP70 gene delivery to the kidney of rats sensitized to HSP70 was associated with increment in blood pressure in response to a high salt diet (88). Several groups, including ourselves, have reported increased circulating anti-HSP70 antibody titers in patients with essential hypertension (27, 85, 88, 110). Hypertensive patients have also increased HSP70 gene expression and HSP70 protein abundance in circulating leukocytes (110) and, in a limited number of patients, we showed that T cells from patients with essential hypertension responded to a challenge with HSP70 with a strong proliferative reaction (88). Li et al. (58) have reported that certain HSP70 gene haplotypes (H5 and H8) are associated with hypertension in the Uygur ethnic minority in China and genome wide association studies have identified single nucleotide polymorphisms of HSPs in the BAT2-BAT5 loci (HSPA1L, HSPA1A, and HSP1B) associated with hypertension (25).

The induction of tolerance to HSP70 has not been evaluated as a therapeutic strategy in patients with essential hypertension. The lack of significant side effects associated with oral HSP60 and derived peptides in clinical trials of prevention of atherosclerosis (32, 50, 128) suggests that a similar approach could be investigated for the treatment of essential hypertension. Future studies on the participation of HSP-driven autoimmunity may bring important insights on the pathogenesis and hopefully treatment of essential hypertension.

Acknowledgements

This review is a part of series of reviews by invitation of Professor László Rosivall, the Editor-in-Chief of Physiology International. It is intended to celebrate the 30th anniversary of establishing the Hungarian Kidney Foundation and 25th anniversary of commencing Budapest Nephrology School, an internationally recognized, annual CME refresher nephrology course.

Conflict of interest

BR-I has no conflict of interest. RJJ is on the Scientific Board of XORT Therapeutics and has patent and patent applications related to lowering uric acid or blocking fructose metabolism in the treatment of hypertension and metabolic disorders.

References

  • 1.

    Ait-Oufella H , Salomon BL , Potteaux S , Robertson AK , Gourdy P , Zoll J , Merval R , Esposito B , Cohen JL , Fisson S , Flavell RA , Hansson GK , Klatzmann D , Tedgui A , Mallat Z : Natural regulatory T cells control the development of atherosclerosis in mice. Nat. Med. 12, 178180 (2006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Almanzar G , Salomon BL , Potteaux S , Robertson AK , Gourdy P , Zoll J , Merval R , Esposito B , Cohen JL , Fisson S , Flavell RA , Hansson GK , Klatzmann D , Tedgui A , Mallat Z : Autoreactive HSP60 epitope-specific T-cells in early human atherosclerotic lesions. J. Autoimmun. 39, 441450 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Amador CA , Barrientos V , Peña J , Herrada AA , González M , Valdés S , Carrasco L , Alzamora R , Figueroa F , Kalergis AM , Michea L : Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes. Hypertension 63, 797803 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Asea A , Kraeft SK , Kurt-Jones EA , Stevenson MA , Chen LB , Finberg RW , Koo GC , Calderwood SK : HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nature Med. 6, 435442 (2000)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Aslanian AM , Chapman HA , Charo IF : Transient role for CD1d-restricted natural killer T cells in the formation of atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 25, 628632 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Bakthisaran R , Tangirala R , Rao ChM : Small heat shock proteins: role in cellular functions and pathology. Biochim. Biophys. Acta 1854, 291319 (2015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Barhoumi T , Kasal DA , Li MW , Shbat L , Laurant P , Neves MF , Paradis P , Schiffrin EL : T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. Hypertension 57, 469476 (2011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Batulan Z , Pulakazhi Venu VK , Li Y , Koumbadinga G , Alvarez-Olmedo DG , Shi C , O’Brien ER : Extracellular release and signaling by Heat Shock Protein 27: role in modifying vascular inflammation. Front. Immunol. 7, 285 (2016). doi:10.3389/fimmu.2016.00285

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Bausinger H , Lipsker D , Ziylan U , Manié S , Briand JP , Cazenave JP , Muller S , Haeuw JF , Ravanat C , de la Salle H , Hanau D : Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur. J. Immunol. 32, 37083713 (2002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Bielecka-Dabrowa A , Barylski M , Mikhailidis DP , Rysz J , Banach M : HSP 70 and atherosclerosis–protector or activator? Expert Opin. Ther. Targets 13, 307317 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Binder CJ , Chang MK , Shaw PX , Miller YI , Hartvigsen K , Dewan A , Witztum JL : Innate and acquired immunity in atherogenesis. Nat. Med. 8, 12181226 (2002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Binder CJ , Hartvigsen K , Chang MK , Miller M , Broide D , Palinski W , Curtiss LK , Corr M , Witztum JL : IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J. Clin. Invest. 114, 427437 (2004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Borst JG , Borst-de Geus A : Hypertension explained by Starling’s theory of circulatory homeostasis. Lancet 1, 677682 (1963)

  • 14.

    Bravo J , Quiroz Y , Pons H , Parra G , Herrera-Acosta J , Johnson RJ , Rodríguez-Iturbe B : Vimentin and heat shock protein expression are induced in the kidney by angiotensin and by nitric oxide inhibition. Kidney Int. 64(Suppl. 86), S46S51 (2003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Buono C , Come CE , Stavrakis G , Maguire GF , Connelly PW , Lichtman AH : T-bet deficiency reduces atherosclerosis and alters plaque antigen specific immune responses. Proc. Natl. Acad. Sci. U S A 102, 15961601 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Calderwood SK : Heat shock proteins in extracellular signaling. Methods 43, 167 (2007)

  • 17.

    Calderwood SK , Gong J , Murshid A : Extracellular HSPs: the complicated roles of extracellular HSPs in immunity. Front. Immunol. 7, 159 (2016). doi:10.3389/fimmu.2016.00159

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Chan CT , Moore JP , Budzyn K , Guida E , Diep H , Vinh A , Jones ES , Widdop RE , Armitage JA , Sakkal S , Ricardo SD , Sobey CG , Drummond GR : Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice. Hypertension 60, 12071212 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Chan CT , Sobey CG , Lieu M , Ferens D , Kett MM , Diep H , Kim HA , Krishnan SM , Lewis CV , Salimova E , Tipping P , Vinh A , Samuel CS , Peter K , Guzik TJ , Kyaw TS , Toh H , Bobik A , Drummond GR : Obligatory role for B cells in the development of angiotensin II-dependent hypertension. Hypertension 66, 10231033 (2015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Cohen IR : Autoantibody repertoires, natural biomarkers, and system controllers. Trends Immunol. 34, 620625 (2013)

  • 21.

    Cuerrier CM , Chen YX , Tremblay D , Rayner K , McNulty M , Zhao X , Kennedy CR , de BelleRoche J , Pelling AE , O’Brien ER : Chronic over-expression of heat shock protein 27 attenuates atherogenesis and enhances plaque remodeling: a combined histological and mechanical assessment of aortic lesions. PLoS One 8, e55867 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Danzaki K , Matsui Y , Ikesue M , Ohta D , Ito K , Kanayama M , Kurotaki D , Morimoto J , Iwakura Y , Yagita H , Tsutsui H , Uede T : Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 32, 273280 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Davenport P , Tipping PG : The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am. J. Pathol. 163, 11171125 (2003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    De Ciuceis C , Amiri F , Brassard P , Endemann DH , Touyz RM , Schiffrin EL : Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury. Arterioscler. Thromb. Vasc. Biol. 25, 21062113 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Ehret GB , Munroe PB , Rice KM , Bochud M , Johnson AD , Chasman DI , Smith AV , Tobin MD , Verwoert GC , Hwang SJ , Pihur V , Vollenweider P , O’Reilly PF , Amin N , Bragg-Gresham JL , Teumer A , Glazer NL , Launer L , Zhao JH , Aulchenko Y , Heath S , Sõber S , Parsa A , Luan J , Arora P , Dehghan A , Zhang F , Lucas G , Hicks AA , Jackson AU , Peden JF , Tanaka T , Wild SH , Rudan I , Igl W , Milaneschi Y , Parker AN , Fava C , Chambers JC , Fox ER , Kumari M , Go MJ , van der Harst P , Kao WH , Sjögren M , Vinay DG , Alexander M , Tabara Y , Shaw-Hawkins S , Whincup PH , Liu Y , Shi G , Kuusisto J , Tayo B , Seielstad M , Sim X , Nguyen KD , Lehtimäki T , Matullo G , Wu Y , Gaunt TR , Onland-Moret NC , Cooper MN , Platou CG , Org E , Hardy R , Dahgam S , Palmen J , Vitart V , Braund PS , Kuznetsova T , Uiterwaal CS , Adeyemo A , Palmas W , Campbell H , Ludwig B , Tomaszewski M , Tzoulaki I , Palmer ND , CARDIoGRAM Consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen Consortium, CHARGE-HF Consortium, Aspelund T, Garcia M, Chang YP, O’Connell JR, Steinle NI, Grobbee DE, Arking DE, Kardia SL, Morrison AC, Hernandez D, Najjar S, McArdle WL, Hadley D, Brown MJ, Connell JM, Hingorani AD, Day IN, Lawlor DA, Beilby JP, Lawrence RW, Clarke R, Hopewell JC, Ongen H, Dreisbach AW, Li Y, Young JH, Bis JC, Kähönen M, Viikari J, Adair LS, Lee NR, Chen MH, Olden M, Pattaro C, Bolton JA, Köttgen A, Bergmann S, Mooser V, Chaturvedi N, Frayling TM, Islam M, Jafar TH, Erdmann J, Kulkarni SR, Bornstein SR, Grässler J, Groop L, Voight BF, Kettunen J, Howard P, Taylor A, Guarrera S, Ricceri F, Emilsson V, Plump A, Barroso I, Khaw KT, Weder AB, Hunt SC, Sun YV, Bergman RN, Collins FS, Bonnycastle LL, Scott LJ, Stringham HM, Peltonen L, Perola M, Vartiainen E, Brand SM, Staessen JA, Wang TJ, Burton PR, Soler Artigas M, Dong Y, Snieder H, Wang X, Zhu H, Lohman KK, Rudock ME, Heckbert SR, Smith NL, Wiggins KL, Doumatey A, Shriner D, Veldre G, Viigimaa M, Kinra S, Prabhakaran D, Tripathy V, Langefeld CD, Rosengren A, Thelle DS, Corsi AM, Singleton A, Forrester T, Hilton G, McKenzie CA, Salako T, Iwai N, Kita Y, Ogihara T, Ohkubo T, Okamura T, Ueshima H, Umemura S, Eyheramendy S, Meitinger T, Wichmann HE, Cho YS, Kim HL, Lee JY, Scott J, Sehmi JS, Zhang W, Hedblad B, Nilsson P, Smith GD, Wong A, Narisu N, Stančáková A, Raffel LJ, Yao J, Kathiresan S, O’Donnell CJ, Schwartz SM, Ikram MA, Longstreth WT Jr, Mosley TH, Seshadri S, Shrine NR, Wain LV, Morken MA, Swift AJ, Laitinen J, Prokopenko I, Zitting P, Cooper JA, Humphries SE, Danesh J, Rasheed A, Goel A, Hamsten A, Watkins H, Bakker SJ, van Gilst WH, Janipalli CS, Mani KR, Yajnik CS, Hofman A, Mattace-Raso FU, Oostra BA, Demirkan A, Isaacs A, Rivadeneira F, Lakatta EG, Orru M, Scuteri A, Ala-Korpela M, Kangas AJ, Lyytikäinen LP, Soininen P, Tukiainen T, Würtz P, Ong RT, Dörr M, Kroemer HK, Völker U, Völzke H, Galan P, Hercberg S, Lathrop M, Zelenika D, Deloukas P, Mangino M, Spector TD, Zhai G, Meschia JF, Nalls MA, Sharma P, Terzic J, Kumar MV, Denniff M, Zukowska-Szczechowska E, Wagenknecht LE, Fowkes FG, Charchar FJ, Schwarz PE, Hayward C, Guo X, Rotimi C, Bots ML, Brand E, Samani NJ, Polasek O, Talmud PJ, Nyberg F, Kuh D, Laan M, Hveem K, Palmer LJ, van der Schouw YT, Casas JP, Mohlke KL, Vineis P, Raitakari O, Ganesh SK, Wong TY, Tai ES, Cooper RS, Laakso M, Rao DC, Harris TB, Morris RW, Dominiczak AF, Kivimaki M, Marmot MG, Miki T, Saleheen D, Chandak GR, Coresh J, Navis G, Salomaa V, Han BG, Zhu X, Kooner JS, Melander O, Ridker PM, Bandinelli S, Gyllensten UB, Wright AF, Wilson JF, Ferrucci L, Farrall M, Tuomilehto J, Pramstaller PP, Elosua R, Soranzo N, Sijbrands EJ, Altshuler D, Loos RJ, Shuldiner AR, Gieger C, Meneton P, Uitterlinden AG, Wareham NJ, Gudnason V, Rotter JI, Rettig R, Uda M, Strachan DP, Witteman JC, Hartikainen AL, Beckmann JS, Boerwinkle E, Vasan RS, Boehnke M, Larson MG, Järvelin MR, Psaty BM, Abecasis GR, Chakravarti A, Elliott P, van Duijn CM, Newton-Cheh C, Levy D, Caulfield MJ, Johnson T: Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103109 (2011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Erbel C , Chen L , Bea F , Wangler S , Celik S , Lasitschka F , Wang Y , Böckler D , Katus HA , Dengler TJ : Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J. Immunol. 183, 81678175 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Frostegärd J , Lemne C , Andersson B , van der Zee R , Kiessling R , de Faire U : Association of serum antibodies to heat-shock protein 65 with borderline hypertension. Hypertension 29, 4044 (1997)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Galdiero M , de l’Ero GC , Marcatili A : Cytokine and adhesion molecule expression in human monocytes and endothelial cells stimulated with bacterial heat shock proteins. Infect. Immun. 65, 699707 (1997)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Gao B , Tsan M-F : Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor release by murine macrophages. J. Biol. Chem. 278, 174179 (2003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Gao Q , Jiang Y , Ma T , Zhu F , Gao F , Zhang P , Guo C , Wang Q , Wang X , Ma C , Zhang Y , Chen W , Zhang L : A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice. J. Immunol. 185, 58205827 (2010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Gomez-Pastor R , Buchfiel ET , Thiele DJ : Regulation of heat shock transcription factors and their roles in physiology and disease. Nat. Rev. Mol. Cell Biol. 19, 419 (2018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Govea-Alonso D , Beltrán-López J , Salazar-González JA , Vargas-Morales J , Rosales-Mendoza S : Progress and future opportunities in the development of vaccines against atherosclerosis. Expert Rev. Vaccines 16, 337350 (2017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Greenstein SM , Sun S , Calderon TM , Kim DY , Schreiber TC , Schechner RS , Tellis VA , Berman JW : Mycophenolate mofetil treatment reduces atherosclerosis in the cholesterol-fed rabbit. J. Surg. Res. 91, 123129 (2000)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Gupta S , Knowlton AA : HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am. J. Physiol. Heart Circ. Physiol. 292, H3052H3056 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Gupta S , Pablo AM , Jiang Xc , Wang N , Tall AR , Schindler C : IFNgamma potentiates atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 27522761 (1997)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Guyton AC , Coleman TG , Cowley AW Jr , Scheel KW , Manning RD Jr , Norman RA Jr : Arterial pressure regulation: overriding dominance of the kidneys in long-term regulation and in hypertension. Am. J. Med. 52, 584594 (1972)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Guzik TJ , Hoch NE , Brown KA , McCann LA , Rahman A , Dikalov S , Goronzy J , Weyand C , Harrison DG : Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Exp. Med. 204, 24492460 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Hansson GK , Libby P , Schönbeck U , Yan ZQ : Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ. Res. 91, 281291 (2002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Ichiyanagi T , Imai T , Kajiwara C , Mizukami S , Nakai A , Nakayama T , Udono H : Essential role of endogenous heat shock protein 90 of dendritic cells in antigen cross-presentation. J. Immunol. 185, 26932700 (2010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Imai T , Kato Y , Kajiwara C , Mizukami S , Ishige I , Ichiyanagi T , Hikida M , Wang JY , Udono H : Heat shock protein 90 (Hsp90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells. Proc. Natl. Acad. Sci. U S A 108, 1636316368 (2011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Itani HA , Xiao L , Saleh MA , Wu J , Pilkinton MA , Dale BL , Barbaro NR , Foss JD , Kirabo A , Montaniel KR , Norlander AE , Chen W , Sato R , Navar LG , Mallal SA , Madhur MS , Bernstein KE , Harrison DG : CD70 exacerbates blood pressure elevation and renal damage in response to repeated hypertensive stimuli. Circ. Res. 118, 12331243 (2016)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Janson AA , Klatser PR , van der Zee R , Cornelisse YE , de Vries RR , Thole JE , Ottenhoff TH : A systematic molecular analysis of the T cell-stimulating antigens from Mycobacterium leprae with T cell clones of leprosy patients. Identification of a novel M. leprae HSP 70 fragment by M. leprae-specific T cells. J. Immunol. 147, 35303537 (1991)

    • Search Google Scholar
    • Export Citation
  • 43.

    Jarosz DF , Lindquist S : Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330, 18201824 (2010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44.

    Jonasson L , Holm J , Skalli O , Bondjers G , Hansson GK : Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 6, 131138 (1986)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45.

    Kampinga HH , Hageman J , Vos MJ , Kubota H , Tanguay RM , Bruford EA , Cheetham ME , Chen B , Hightower LE : Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14, 105111 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46.

    Kanwar RK , Kanwar JR , Wang D , Ormrod DJ , Krissansen GW : Temporal expression of heat shock proteins 60 and 70 at lesion-prone sites during atherogenesis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 21, 19911997 (2001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    Kaufmann SH , Vath U , Thole JE , Van Embden JD , Emmrich F : Enumeration of T cells reactive with Mycobacterium tuberculosis organisms and specific for the recombinant mycobacterial 64-kDa protein. Eur. J. Immunol. 17, 351357 (1987)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48.

    Ketelhuth DF , Hansson GK : Cellular immunity, low-density lipoprotein and atherosclerosis: break of tolerance in the artery wall. Thromb. Haemost. 106, 779786 (2011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49.

    Ketelhuth DFJ , Hansson DK : Adaptive responses of T and B cells in atherosclerosis. Circ. Res. 118, 668678 (2016)

  • 50.

    Kimura T , Tse K , Sette A , Ley K : Vaccination to modulate atherosclerosis. Autoimmunity 48, 152160 (2015)

  • 51.

    King VL , Szilvassy SJ , Daugherty A : Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor-/- mice. Arterioscler. Thromb. Vasc. Biol. 22, 456461 (2002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52.

    Kirabo A , Fontana V , de Faria AP , Loperena R , Galindo CL , Wu J , Bikineyeva AT , Dikalov S , Xiao L , Chen W , Saleh MA , Trott DW , Itani HA , Vinh A , Amarnath V , Amarnath K , Guzik TJ , Bernstein KE , Shen XZ , Shyr Y , Chen SC , Mernaugh RL , Laffer CL , Elijovich F , Davies SS , Moreno H , Madhur MS , Roberts J 2nd , Harrison DG : DC isoketal-modified proteins activate T cells and promote hypertension. J. Clin. Invest. 124, 46424656 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53.

    Knoflach M , Kiechl S , Mayrl B , Kind M , Gaston JS , van der Zee R , Faggionato A , Mayr A , Willeit J , Wick G : T-cell reactivity against HSP60 relates to early but not advanced atherosclerosis. Atherosclerosis 195, 333338 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54.

    Kol A , Bourcier T , Lichtman A , Libby P : Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J. Clin. Invest. 103, 571577 (1999)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55.

    Kregel KC : Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J. Appl. Physiol. 92, 21772186 (2002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56.

    Kyaw T , Winship A , Tay C , Kanellakis P , Hosseini H , Cao A , Li P , Tipping P , Bobik A , Toh BH : Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in apoE-deficient mice. Circulation 127, 10281039 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57.

    Lancaster GI , Febbraio MA : Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J. Biol. Chem. 280, 2334923355 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58.

    Li JX , Tang BP , Sun HP , Feng M , Cheng ZH , Niu WQ : Interacting contribution of the five polymorphisms in three genes of Hsp70 family to essential hypertension in Uygur ethnicity. Cell Stress Chaperones 14, 355362 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 59.

    Liang M , Cowley AW Jr , Mattson DL , Kotchen TA , Liu Y : Epigenomics of hypertension. Semin. Nephrol. 33, 392399 (2013)

  • 60.

    Lim SS , Vos T , Flaxman AD , Danaei G , Shibuya K , Adair-Rohani H , Amann M , Anderson HR , Andrews KG , Aryee M , Atkinson C , Bacchus LJ , Bahalim AN , Balakrishnan K , Balmes J , Barker-Collo S , Baxter A , Bell ML , Blore JD , Blyth F , Bonner C , Borges G , Bourne R , Boussinesq M , Brauer M , Brooks P , Bruce NG , Brunekreef B , Bryan-Hancock C , Bucello C , Buchbinder R , Bull F , Burnett RT , Byers TE , Calabria B , Carapetis J , Carnahan E , Chafe Z , Charlson F , Chen H , Chen JS , Cheng AT , Child JC , Cohen A , Colson KE , Cowie BC , Darby S , Darling S , Davis A , Degenhardt L , Dentener F , Des Jarlais DC , Devries K , Dherani M , Ding EL , Dorsey ER , Driscoll T , Edmond K , Ali SE , Engell RE , Erwin PJ , Fahimi S , Falder G , Farzadfar F , Ferrari A , Finucane MM , Flaxman S , Fowkes FG , Freedman G , Freeman MK , Gakidou E , Ghosh S , Giovannucci E , Gmel G , Graham K , Grainger R , Grant B , Gunnell D , Gutierrez HR , Hall W , Hoek HW , Hogan A , Hosgood HD 3rd , Hoy D , Hu H , Hubbell BJ , Hutchings SJ , Ibeanusi SE , Jacklyn GL , Jasrasaria R , Jonas JB , Kan H , Kanis JA , Kassebaum N , Kawakami N , Khang YH , Khatibzadeh S , Khoo JP , Kok C , Laden F , Lalloo R , Lan Q , Lathlean T , Leasher JL , Leigh J , Li Y , Lin JK , Lipshultz SE , London S , Lozano R , Lu Y , Mak J , Malekzadeh R , Mallinger L , Marcenes W , March L , Marks R , Martin R , McGale P , McGrath J , Mehta S , Mensah GA , Merriman TR , Micha R , Michaud C , Mishra V , Mohd Hanafiah K , Mokdad AA , Morawska L , Mozaffarian D , Murphy T , Naghavi M , Neal B , Nelson PK , Nolla JM , Norman R , Olives C , Omer SB , Orchard J , Osborne R , Ostro B , Page A , Pandey KD , Parry CD , Passmore E , Patra J , Pearce N , Pelizzari PM , Petzold M , Phillips MR , Pope D , Pope CA 3rd , Powles J , Rao M , Razavi H , Rehfuess EA , Rehm JT , Ritz B , Rivara FP , Roberts T , Robinson C , Rodriguez-Portales JA , Romieu I , Room R , Rosenfeld LC , Roy A , Rushton L , Salomon JA , Sampson U , Sanchez-Riera L , Sanman E , Sapkota A , Seedat S , Shi P , Shield K , Shivakoti R , Singh GM , Sleet DA , Smith E , Smith KR , Stapelberg NJ , Steenland K , Stöckl H , Stovner LJ , Straif K , Straney L , Thurston GD , Tran JH , Van Dingenen R , van Donkelaar A , Veerman JL , Vijayakumar L , Weintraub R , Weissman MM , White RA , Whiteford H , Wiersma ST , Wilkinson JD , Williams HC , Williams W , Wilson N , Woolf AD , Yip P , Zielinski JM , Lopez AD , Murray CJ , Ezzati M , AlMazroa MA , Memish ZA : A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 22242260 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 61.

    Lu X , Xia M , Endresz V , Faludi I , Szabo A , Gonczol E , Mundkur L , Chen D , Kakkar V : Impact of multiple antigenic epitopes from ApoB100, hHSP60 and Chlamydophila pneumoniae on atherosclerotic lesion development. Atherosclerosis 225, 5668 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 62.

    Madrigal-Matute J , López-Franco O , Blanco-Colio LM , Muñoz-García B , Ramos-Mozo P , Ortega L , Egido J , Martín-Ventura JL : Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis. Cardiovasc. Res. 86, 330337 (2010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 63.

    Majeed B , Tawinwung S , Eberson LS , Secomb TW , Larmonier N , Larson DF : Interleukin-2/anti-interleukin-2 immune complex expands regulatory T cells and reduces angiotensin II-induced aortic stiffening. Int. J. Hypertens. 2014, 126365 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 64.

    Mambula SS , Calderwood SK : Heat induced release of Hsp70 from prostate carcinoma cells involves both active secretion and passive release from necrotic cells. Int. J. Hyperthermia 22, 575585 (2006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 65.

    Mambula SS , Calderwood SK : Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J. Immunol. 177, 78497857 (2006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 66.

    Marincek B-C , Kühnle MC , Srokowski C , Schild H , Hämmerling G , Momburg F : Heat shock protein-antigen fusions lose their enhanced immuno-stimulatory capacity after endotoxin depletion. Mol. Immunol. 46, 181191 (2008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 67.

    Martin-Ventura JL , Duran MC , Blanco-Colio LM , Meilhac O , Leclercq A , Michel JB , Jensen ON , Hernandez-Merida S , Tuñón J , Vivanco F , Egido J : Identification by a differential proteomic approach of heat shock protein 27 as a potential marker of atherosclerosis. Circulation 110, 22162219 (2004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 68.

    Martin-Ventura JL , Leclercq A , Blanco-Colio LM , Egido J , Rossignol P , Meilhac O , Michel JB : Low plasma levels of HSP70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation. Atherosclerosis 194, 334341 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 69.

    Matthews RC , Maresca B , Burnie JP , Cardona A , Carratu L , Conti S , Deepe GS , Florez AM , Franceschelli S , Garcia E , Gargano LS , Kobayashi GS , McEwen JG , Ortiz BL , Oviedo AM , Polonelli L , Ponton J , Restrepos A , Storlazzi A : Stress proteins in fungal diseases. Med. Mycol. 36(Suppl. 1), 4551 (1998)

    • Search Google Scholar
    • Export Citation
  • 70.

    Mattson DL , Lund H , Guo C , Rudemiller N , Geurts AM , Jacob H : Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R407R414 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 71.

    Mayerl C , Lukasser M , Sedivy R , Niederegger H , Seiler R , Wick G : Atherosclerosis research from past to present – on the track of two pathologists with opposing views, Carl von Rokitansky and Rudolf Virchow. Virchows Arch. 449, 96103 (2006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 72.

    Menoret A , Chandawarkar RY , Srivastava PK : Natural autoantibodies against heat-shock proteins hsp70 and gp96: implications for immunotherapy using heat-shock proteins. Immunology 101, 364370 (2000)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 73.

    Mian MO , Barhoumi T , Briet M , Paradis P , Schiffrin EL : Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses. J. Hypertens. 34, 97108 (2016)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 74.

    Millar LN , Murrell GAC : Heat shock proteins in tendinopathy: novel molecular regulators. Mediators Inflamm. 2012, 436203 (2012)

  • 75.

    Miller H , Poon S , Hibbert B , Rayner K , Chen YX , O’Brien ER : Modulation of estrogen signaling by the novel interaction of heat shock protein 27, a biomarker for atherosclerosis, and estrogen receptor beta: mechanistic insight into the vascular effects of estrogens. Arterioscler. Thromb. Vasc. Biol. 25, e10e14 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 76.

    Mohanta SK , Yin C , Peng L , Srikakulapu P , Bontha V , Hu D , Weih F , Weber C , Gerdes N , Habenicht AJ : Artery tertiary lymphoid organs contribute to innate and adaptive immune responses in advanced mouse atherosclerosis. Circ. Res. 114, 17721787 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 77.

    Munroe PB , Barnes MR , Caulfield MJ : Advances in blood pressure genomics. Circ. Res. 112, 13651379 (2013)

  • 78.

    Nègre-Salvayre A , Augé N , Camaré C , Bacchetti T , Ferretti G , Salvayre R : Dual signaling evoked by oxidized LDLs in vascular cells. Free Radic. Biol. Med. 106, 118133 (2017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 79.

    Nickel W , Seedorf M : Unconventional mechanisms of protein transport to the cell surface of eukaryotic cells. Annu. Rev. Cell Dev. Biol. 24, 287308 (2008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 80.

    Norlander AE , Saleh MA , Kamat NV , Ko B , Gnecco J , Zhu L , Dale BL , Iwakura Y , Hoover RS , McDonough AA , Madhur MS : Interleukin-17A regulates renal sodium transporters and renal injury in angiotensin II-induced hypertension. Hypertension 68, 167174 (2016)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 81.

    Ohashi K , Burkart V , Flohé S , Kolb H : Heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164, 558561 (2000)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 82.

    Parra G , Quiroz Y , Salazar J , Bravo Y , Pons H , Chavez M , Johnson RJ , Rodriguez-Iturbe B : Experimental induction of salt-sensitive hypertension is associated with lymphocyte proliferative response to HSP70. Kidney Int. 74(Suppl. 111), S55S59 (2008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 83.

    Pockley AG : Heat shock proteins as regulators of the immune response. Lancet 362, 469476 (2003)

  • 84.

    Pockley AG , Bulmer J , Hanks BM , Wright BH : Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals. Cell Stress Chaperones 4, 2935 (1999)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 85.

    Pockley AG , De Faire U , Kiessling R , Lemne C , Thulin T , Frostegård J : Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J. Hypertens. 20, 18151820 (2002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 86.

    Pockley AG , Shepherd J , Corton J : Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol. Invest. 27, 367377 (1998)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 87.

    Pockley AG , Wu R , Lemne C , Kiessling R , de Faire U , Frostegard J : Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension 36, 303307 (2000)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 88.

    Pons H , Ferrebuz A , Quiroz Y , Romero-Vasquez F , Parra G , Johnson RJ , Rodriguez-Iturbe B : Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt sensitive hypertension. Am. J. Physiol. Renal Physiol. 304, F289F299 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 89.

    Poulter NR , Prabhakaran D , Caulfield M : Hypertension. Lancet 386, 801812 (2015)

  • 90.

    Powers ET , Morimoto RI , Dillin A , Kelly JW , Balch WE : Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959991 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 91.

    Rayner K , Chen YX , McNulty M , Simard T , Zhao X , Wells DJ , de Belleroche J , O’Brien ER : Extracellular release of the atheroprotective heat shock protein 27 is mediated by estrogen and competitively inhibits acLDL binding to scavenger receptor-A. Circ. Res. 103, 133141 (2008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 92.

    Retzlaff C , Yamamoto Y , Hoffman PS , Friedman H , Klein TW : Bacterial heat shock proteins directly induce cytokine mRNA and interleukin-1 secretion in macrophage cultures. Infect. Immun. 62, 56895693 (1994)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 93.

    Ridker PM , Everett BM , Thuren T , MacFadyen JG , Chang WH , Ballantyne C , Fonseca F , Nicolau J , Koenig W , Anker SD , Kastelein JJP , Cornel JH , Pais P , Pella D , Genest J , Cifkova R , Lorenzatti A , Forster T , Kobalava Z , Vida-Simiti L , Flather M , Shimokawa H , Ogawa H , Dellborg M , Rossi PRF , Troquay RPT , Libby P , Glynn RJ , CANTOS Trial Group: Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 11191131 (2017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 94.

    Ritossa F : A new puffing pattern induced by temperature and DNP in Drosophila. Experientia 18, 571573 (1962)

  • 95.

    Rodriguez-Iturbe B , Johnson RJ : The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension. Hypertens. Res. 33, 975980 (2010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 96.

    Rodriguez-Iturbe B , Pons H , Johnson RJ : The role of the immune system in hypertension. Physiol. Rev. 97, 11271164 (2017)

  • 97.

    Rodriguez-Iturbe B , Pons H , Quiroz Y , Johnson RJ : The immunological basis of hypertension. Am. J. Hypertens. 27, 13271337 (2014)

  • 98.

    Rodriguez-Iturbe B , Vaziri ND , Herrera-Acosta J , Johnson RJ : Oxidative stress, renal infiltration of immune cells and salt-sensitive hypertension: all for one and one for all. Am. J. Physiol. Renal Physiol. 286, F606F616 (2004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 99.

    Romero F , Rodríguez-Iturbe B , Pons H , Parra G , Quiroz Y , Rincón J , González L : Mycophenolate mofetil treatment reduces cholesterol-induced atherosclerosis in the rabbit. Atherosclerosis 152, 127133 (2000)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 100.

    Ross R : Atherosclerosis – an inflammatory disease. N. Engl. J. Med. 340, 115126 (1999)

  • 101.

    Rudemiller NP , Lund H , Jacob HJ , Geurts AM , Mattson DL : CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension 63, 559564 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 102.

    Rutherford SL , Lindquist S : Hsp90 as a capacitor for morphological evolution. Nature 396, 336342 (1998)

  • 103.

    Salari S , Seibert T , Chen YX , Hu T , Shi C , Zhao X , Cuerrier CM , Raizman JE , O’Brien ER : Extracellular HSP27 acts as a signaling molecule to activate NF-kappa B in macrophages. Cell Stress Chaperones 18, 5363 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 104.

    Sanchez-Campillo M , Bini L , Comanducci M , Raggiaschi R , Marzocchi B , Pallini V , Ratti G : Identification of immunoreactive proteins of Chlamydia trachomatis by Western blot analysis of a two-dimensional electrophoresis map with patient sera. Electrophoresis 20, 22692279 (1999)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 105.

    Schopf FH , Biebl MM , Buchner J : The HSP90 chaperone machinery. Nat. Rev. Mol. Cell Biol. 18, 345360 (2017)

  • 106.

    Seibert TA , Hibbert B , Chen YX , Rayner K , Simard T , Hu T , Cuerrier CM , Zhao X , de Belleroche J , Chow BJ , Hawken S , Wilson KR , O’Brien ER : Serum heat shock protein 27 levels represent a potential therapeutic target for atherosclerosis: observations from a human cohort and treatment of female mice. J. Am. Coll. Cardiol. 62, 14461454 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 107.

    Shinnick TM : Heat shock proteins as antigens of bacterial and parasitic pathogens. Curr. Top. Microbiol. Immunol. 167, 145160 (1991)

    • Search Google Scholar
    • Export Citation
  • 108.

    Shinnick TM , Vodkin MH , Williams JC : The Mycobacterium tuberculosis 65-kilodalton antigen is a heat shock protein which corresponds to common antigen and to the Escherichia coli GroEL protein. Infect. Immun. 56, 446451 (1988)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 109.

    Smith E , Prasad KM , Butcher M , Dobrian A , Kolls JK , Ley K , Galkina E : Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 121, 17461755 (2010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 110.

    Srivastava K , Narang R , Bhatia J , Saluja D : Expression of heat shock protein 70 gene and its correlation with inflammatory markers in essential hypertension. PLoS One 11(3), e0151060 (2016)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 111.

    Tabas I , Litchman AH : Monocytes-macrophages and T cells in atherosclerosis. Immunity 47, 621634 (2017)

  • 112.

    Taleb S , Romain M , Ramkhelawon B , Uyttenhove C , Pasterkamp G , Herbin O , Esposito B , Perez N , Yasukawa H , Van Snick J , Yoshimura A , Tedgui A , Mallat Z : Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J. Exp. Med. 206, 20672077 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 113.

    Tissières A , Mitchell HK , Tracy U : Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J. Mol. Biol. 84, 389398 (1974)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 114.

    Trott DW , Thabet SR , Kirabo A , Saleh MA , Itani H , Norlander AE , Wu J , Goldstein A , Arendshorst WJ , Madhur MS , Chen W , Li CI , Shyr Y , Harrison DG : Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 64, 11081115 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 115.

    Vabulas RM , Ahmad-Nejad P , da Costa C , Miethke T , Kirschning CJ , Häcker H , Wagner H : Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J. Biol. Chem. 276, 3133231339 (2001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 116.

    Van Dyk TK , Majarian WR , Konstantinov KB , Young RM , Dhurjati PS , LaRossa RA : Rapid and sensitive pollutant detection by induction of heat shock gene-bioluminescence gene fusions. Appl. Environ. Microbiol. 60, 14141420 (1994)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 117.

    van Eden W , Holoshitz J , Nevo Z , Frenkel A , Klajman A , Cohen IR : Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc. Natl. Acad. Sci. U S A 82, 51175120 (1985)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 118.

    van Eden W , Koets A , van Kooten P , Prakken B , van der Zee R : Immunopotentiating heat shock proteins: negotiators between danger and control of autoimmunity. Vaccine 21, 897901 (2003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 119.

    van Eden W , Tholet JER , van der Zee R , Noordzij A , van Embden JDA : Cloning of mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 331, 171173 (1988)