Low levels of testosterone in men with diabetes are associated with cardiovascular complications. We investigated the effect of testosterone and voluntary exercise on heart angiogenesis in castrated diabetic rats.
Sixty-three diabetic rats were treated with testosterone 2 mg/kg/day or voluntary exercise alone or combination of these two for 6 weeks. At the end of the study, heart tissue samples were collected and used for CD31 detection by immunohistochemical method and determination of miR-132 levels.
miR-132 levels and CD31 of heart tissue were higher after testosterone administration and in the voluntary exercise group in diabetic rats after 6 weeks. Combination of testosterone and voluntary exercise had synergistic effect on angiogenesis and miR-132 level. In castrated diabetic rats, there were significantly lower levels of miR-132 and CD31 in heart tissue compared to the diabetic group, whereas testosterone and exercise reversed these effects. In addition, testosterone supplementation plus exercise had an additive effect on miR-132 levels and CD31 in castrated diabetic rats.
It was concluded that castration in rats leads to reduced miR-132 levels and subsequently decreased angiogenesis in diabetes. Testosterone plus voluntary exercise improved angiogenesis possibly through enhancement of miR-132 levels in heart of castrated diabetic rats.
Anand S , Majeti BK , Acevedo LM , Murphy EA , Mukthavaram R , Scheppke L , Huang M , Shields DJ , Lindquist JN , Lapinski PE , King PD , Weis SM , Cheresh DA : MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat. Med. 16, 909–914 (2010)
Aronson D (2008): Hyperglycemia and the pathobiology of diabetic complications. In: Cardiovascular Diabetology: Clinical, Metabolic and Inflammatory Facets, vol 45, eds Fisman EZ, Tenenbaum A, Karger Publishers, Basel, Switzerland, pp. 1–16
Bebb R , Millar A , Brock G , Diabetes Canada Clinical Practice Guidelines Expert Committee : Sexual dysfunction and hypogonadism in men with diabetes. Can. J. Diabetes. 42, S228–S233 (2018)
Bhasin S , Storer TW , Berman N , Callegari C , Clevenger B , Phillips J , Bunnell TJ , Tricker R , Shirazi A , Casaburi R : The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N. Engl. J. Med. 335, 1–7 (1996)
Bianchi VE : Testosterone, myocardial function, and mortality. Heart Fail. Rev. 23, 773–788 (2018)
Chen Y , Fu L , Han Y , Teng Y , Sun J , Xie R , Cao J : Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF. Eur. J. Pharmacol. 684, 116–124 (2012)
Cho N , Shaw J , Karuranga S , Huang Y , da Rocha Fernandes J , Ohlrogge A , Malanda B : IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 138, 271–281 (2018)
Chodari L , Mohammadi M , Ghorbanzadeh V , Dariushnejad H , Mohaddes G : Testosterone and voluntary exercise promote angiogenesis in hearts of rats with diabetes by enhancing expression of VEGF-A and SDF-1a. Can. J. Diabetes 40, 436–441 (2016)
Chodari L , Mohammadi M , Mohaddes G , Alipour MR , Ghorbanzade V , Dariushnejad H , Mohammadi S : Testosterone and voluntary exercise, alone or together increase cardiac activation of AKT and ERK1/2 in diabetic rats. Arq. Bras. Cardiol. 107, 532–541 (2016)
Chronic Kidney Disease Prognosis Consortium , Matsushita K , van der Velde M , Astor BC , Woodward M , Levey AS , de Jong PE , Coresh J , Gansevoort RT : Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375, 2073–2081 (2010)
Costa PZ , Soares R : Neovascularization in diabetes and its complications. Unraveling the angiogenic paradox. Life Sci. 92, 1037–1045 (2013)
Dos Santos M , Sayegh A , Bacurau A , Arap MA , Brum PC , Pereira RM , Takayama L , Barretto AC , Negrão CE , Alves MJ : Effect of testosterone treatment and exercise on muscle wasting in patients with heart failure with testosterone deficiency. Mayo Clin. Proc. 91, 575–586 (2017)
Dunford EC , Leclair E , Aiken J , Mandel ER , Haas TL , Birot O , Riddell MC : The effects of voluntary exercise and prazosin on capillary rarefaction and metabolism in streptozotocin-induced diabetic male rats. J. Appl. Physiol. 122, 492–502 (2016)
Esser KA , Su W , Matveev S , Wong V , Zeng L , McCarthy JJ , Smart EJ , Guo Z , Gong MC : Voluntary wheel running ameliorates vascular smooth muscle hyper-contractility in type 2 diabetic db/db mice. Appl. Physiol. Nutr. Metab. 32, 711–720 (2007)
Ghorbanzadeh V , Mohammadi M , Dariushnejad H , Abhari A , Chodari L , Mohaddes G : Cardioprotective effect of crocin combined with voluntary exercise in rat: role of miR-126 and miR-210 in heart angiogenesis. Arq. Bras. Cardiol. 109, 54–62 (2017)
Ghorbanzadeh V , Mohammadi M , Mohaddes G , Dariushnejad H , Chodari L , Mohammadi S : Protective effect of crocin and voluntary exercise against oxidative stress in the heart of high-fat diet-induced type 2 diabetic rats. Physiol. Int. 103, 459–468 (2016)
Gregg EW , Gerzoff RB , Caspersen CJ , Williamson DF , Narayan KV : Relationship of walking to mortality among US adults with diabetes. Arch. Intern. Med. 163, 1440–1447 (2003)
Hildreth KL , Barry DW , Moreau KL , Vande Griend J , Meacham RB , Nakamura T , Wolfe P , Kohrt WM , Ruscin JM , Kittelson J , Cress ME , Ballard R , Schwartz RS : Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J. Clin. Endocrinol. Metab. 98, 1891–1900 (2013)
Kanter M , Aksu F , Takir M , Kostek O , Kanter B , Oymagil A : Effects of low intensity exercise against apoptosis and oxidative stress in streptozotocin-induced diabetic rat heart. Exp. Clin. Endocrinol. Diabetes 125, 583–591 (2017)
Katare R , Riu F , Mitchell K , Gubernator M , Campagnolo P , Cui Y , Fortunato O , Avolio E , Cesselli D , Beltrami AP , Angelini G , Emanueli C , Madeddu P : Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132. Circ. Res. 109, 894–906 (2011)
Malkin CJ , Pugh PJ , Morris PD , Kerry KE , Jones RD , Jones TH , Channer KS : Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart 90, 871–876 (2004)
Mohammadian F , Abhari A , Dariushnejad H , Zarghami F , Nikanfar A , Pilehvar-Soltanahmadi Y , Zarghami N : Upregulation of Mir-34a in AGS gastric cancer cells by a PLGA-PEG-PLGA chrysin nano formulation. Asian Pac. J. Cancer Prev. 16, 8259–8263 (2015)
Mulik S , Xu J , Reddy PB , Rajasagi NK , Gimenez F , Sharma S , Lu PY , Rouse BT : Role of miR-132 in angiogenesis after ocular infection with herpes simplex virus. Am. J. Pathol. 181, 525–534 (2012)
Ozougwu J , Obimba K , Belonwu C , Unakalamba C : The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J. Physiol. Pathophysiol. 4, 46–57 (2013)
Prakash R , Somanath PR , El-Remessy AB , Kelly-Cobbs A , Stern JE , Dore-Duffy P , Johnson M , Fagan SC , Ergul A : Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling. Diabetes 61, 1533–1542 (2012)
Rawal S , Munasinghe PE , Shindikar A , Paulin J , Cameron V , Manning P , Williams MJ , Jones GT , Bunton R , Galvin I , Katare R : Down-regulation of proangiogenic microRNA-126 and microRNA-132 are early modulators of diabetic cardiac microangiopathy. Cardiovasc. Res. 113, 90–101 (2017)
Rovira-Llopis S , Bañuls C , de Marañon AM , Diaz-Morales N , Jover A , Garzon S , Rocha M , Victor VM , Hernandez-Mijares A : Low testosterone levels are related to oxidative stress, mitochondrial dysfunction and altered subclinical atherosclerotic markers in type 2 diabetic male patients. Free Radic. Biol. Med. 108, 155–162 (2017)
Schulster M , Bernie AM , Ramasamy R : The role of estradiol in male reproductive function. Asian J. Androl. 18, 435 (2016)
Sieveking D , Lim P , Ng M , Celermajer D : A novel role for androgens in angiogenesis and endothelial progenitor cell mobilisation. Heart Lung Circ. 17, S4 (2008)
Sieveking DP , Lim P , Chow RW , Dunn LL , Bao S , McGrath KC , Heather AK , Handelsman DJ , Celermajer DS , Ng MK : A sex-specific role for androgens in angiogenesis. J. Exp. Med. 207, 345–352 (2010)
Toedebusch R , Belenchia A , Pulakat L : Diabetic cardiomyopathy: impact of biological sex on disease development and molecular signatures. Front. Physiol. 9, 453 (2018)
Tsalouhidou S , Petridou A , Mougios V : Effect of chronic exercise on DNA fragmentation and on lipid profiles in rat skeletal muscle. Exp. Physiol. 94, 362–370 (2009)
Van Dam EW , Dekker JM , Lentjes EG , Romijn FP , Smulders YM , Post WJ , Romijn JA , Krans HM : Steroids in adult men with type 1 diabetes: a tendency to hypogonadism. Diabetes Care. 26, 1812–1818 (2003)
van Rooij E : The art of microRNA research. Circ. Res. 108, 219–234 (2011)
Vo N , Klein ME , Varlamova O , Keller DM , Yamamoto T , Goodman RH , Impey S : A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc. Natl. Acad. Sci. U. S. A. 102, 16426–16431 (2005)
Xu Q , Wells CC , Garman JH , Asico L , Escano CS , Maric C : Imbalance in sex hormone levels exacerbates diabetic renal disease. Hypertension 51, 1218–1224 (2008)