Abstract
BackgroundIn clinical studies, myocardial remodeling in aortic valve stenosis appears to be more favorable in women than in men, even after menopause. In the present study, we assessed whether circulating androgens contribute to a less favorable myocardial remodeling under pressure overload in males. We examined sex-related differences in one-year-old male and female mice. Whereas male mice at this age exhibited circulating androgen levels within the normal range for young adults, the circulating estrogens in females were reduced. The contribution of gonadal androgens to cardiac remodeling was analyzed in a group of same-age castrated mice.Methodology/Principal FindingsAnimals were subjected to transverse aortic constriction (TAC). Echocardiography was performed 2 weeks after TAC and myocardial mRNA levels of TGF-βs, Smads 2 and 3, collagens, fibronectin, β-myosin heavy chain and α-myosin heavy chain were determined by q-PCR. Protein detection of p-SMAD2/3 was performed by Western Blot. Histological staining of fibrosis was performed with picrosirius red and Masson's trichrome. Compared with females, males developed more severe tissue fibrosis, LV dilation and hemodynamic dysfunction. TAC-males showed higher myocardial expression levels of TGF-βs and the treatment with a neutralizing antibody to TGF-β prevented myocardial fibrosis development. Orchiectomy diminished TAC-induced up-regulation of TGF-βs and TGF-β target genes, and it also reduced fibrosis and hemodynamic dysfunction. The capability of androgens to induce TGF-β expression was confirmed in NIH-3T3 fibroblasts and H9C2 cardiomyocytes exposed to dihydrotestosterone.Conclusions/SignificanceOur results indicate that circulating androgens are responsible for the detrimental effects in the myocardium of older male mice subjected to pressure overload through a mechanism involving TGF-βs.
Highlights
Degenerative aortic valve stenosis (AS) is a common cardiovascular disorder and the most prevalent acquired valvular disease in Western countries [1]
Sex-related differences in myocardial remodeling have been observed repeatedly in patients with left ventricular (LV) pressure overload produced by AS [9,10,11,12,13,14,15]
These clinical observations were obtained from older patients, experimental studies addressing sex differences in LV remodeling were typically performed in young animals [28,29]
Summary
Degenerative aortic valve stenosis (AS) is a common cardiovascular disorder and the most prevalent acquired valvular disease in Western countries [1] In this pathology, the chronic pressureoverload condition causes left ventricular (LV) remodeling that is characterized by the hypertrophic growth of cardiomyocytes, proliferation of cardiac fibroblasts, increased deposition of extracellular matrix constituents, and loss of myocytes with fibrotic replacement. Clinical studies on AS patients, showed that LV remodeling occurs differently in postmenopausal women, who lack the putative estrogen-dependent cardiovascular protection, than in older men, many of whom have circulating testosterone levels that would fall within the normal range for young men [9,10,11,12,13] This observation suggests that circulating androgens may be involved in the less favorable remodeling reported in male AS patients. The contribution of gonadal androgens to cardiac remodeling was analyzed in a group of same-age castrated mice
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