View More View Less
  • 1 Urmia University of Medical Sciences, Iran
  • | 2 Urmia University of Medical Sciences, Iran
  • | 3 Lorestan University of Medical Sciences, Iran
  • | 4 Lorestan University of Medical Sciences, Iran
Restricted access

Purchase article

USD  $25.00

1 year subscription (Individual Only)

USD  $752.00

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

  • 1.

    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, 909914 (2010)

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

    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. 116

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

    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, S228S233 (2018)

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

    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, 17 (1996)

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

    Bianchi VE : Testosterone, myocardial function, and mortality. Heart Fail. Rev. 23, 773788 (2018)

  • 6.

    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, 116124 (2012)

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

    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, 271281 (2018)

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

    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, 436441 (2016)

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

    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, 532541 (2016)

    • Search Google Scholar
    • Export Citation
  • 10.

    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, 20732081 (2010)

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

    Costa PZ , Soares R : Neovascularization in diabetes and its complications. Unraveling the angiogenic paradox. Life Sci. 92, 10371045 (2013)

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

    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, 575586 (2017)

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

    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, 492502 (2016)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    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, 711720 (2007)

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

    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, 5462 (2017)

    • Search Google Scholar
    • Export Citation
  • 16.

    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, 459468 (2016)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Gregg EW , Gerzoff RB , Caspersen CJ , Williamson DF , Narayan KV : Relationship of walking to mortality among US adults with diabetes. Arch. Intern. Med. 163, 14401447 (2003)

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

    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, 18911900 (2013)

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

    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, 583591 (2017)

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

    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, 894906 (2011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    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, 871876 (2004)

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

    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, 82598263 (2015)

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

    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, 525534 (2012)

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

    Ozougwu J , Obimba K , Belonwu C , Unakalamba C : The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J. Physiol. Pathophysiol. 4, 4657 (2013)

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

    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, 15331542 (2012)

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

    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, 90101 (2017)

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

    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, 155162 (2017)

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

    Schulster M , Bernie AM , Ramasamy R : The role of estradiol in male reproductive function. Asian J. Androl. 18, 435 (2016)

  • 29.

    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)

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

    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, 345352 (2010)

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

    Toedebusch R , Belenchia A , Pulakat L : Diabetic cardiomyopathy: impact of biological sex on disease development and molecular signatures. Front. Physiol. 9, 453 (2018)

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

    Tsalouhidou S , Petridou A , Mougios V : Effect of chronic exercise on DNA fragmentation and on lipid profiles in rat skeletal muscle. Exp. Physiol. 94, 362370 (2009)

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

    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, 18121818 (2003)

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

    van Rooij E : The art of microRNA research. Circ. Res. 108, 219234 (2011)

  • 35.

    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, 1642616431 (2005)

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

    Xu Q , Wells CC , Garman JH , Asico L , Escano CS , Maric C : Imbalance in sex hormone levels exacerbates diabetic renal disease. Hypertension 51, 12181224 (2008)

    • Crossref
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 237 237 18
Full Text Views 41 3 0
PDF Downloads 23 2 0