New gender specific insights into myocardial remodelling in human aortic valve stenosis
Zusammenfassung der Projektergebnisse
Women with aortic stenosis (AS) undergoing aortic valve replacement exhibited faster regression of myocardial hypertrophy than men. In intra-operative biopsies from male patients, pro-fibrotic gene expression was stronger induced than in females. 17ß-Estradiol (E2) increased mRNA expression of collagen I and III in cardiac fibroblasts from male rats and decreased collagen expression in females. Therefore we hypothesized that a sexspecific regulation in cardiac fibrosis, partially mediated by E2, could explain sex-differences in myocardial adaption and regression with clinical relevance. The aim of our study was to continue the prospective clinical study of patients with isolated AS undergoing aortic valve replacement. We continued the characterization of sexdifferences in left ventricular morphology and function and systematic follow up. We wanted to further analyze sex-differences in extracellular matrix regulation in intra-operative biopsies from men and women with AS and target the underlying mechanisms for E2/ER mediated sex-differences in collagen expression in adult rat cardiac fibroblasts. So far we included 51 new patients (32 men/ 19 women). Follow up has been obtained from 106 patients (53 men/ 53 women). Echocardiography follow up measurements from 52 patients (29 men/ 23 women) are available. So far, intra-operative biopsies from 12 male and 17 female new AS patients have been obtained and histochemical analysis for cardiac fibrosis and apoptosis are under way. In isolated rat cardiac fibroblasts, sex-specific regulation of collagen I and III by E2 is altered in the same direction at mRNA and protein level. Our data indicate that ERα is responsible for E2-mediated down-regulation of collagen I and III mRNA in cells obtained from female, but not male rats. Indeed, ERα is phosphorylated at ser118 by E2 only in cardiac fibroblasts from females. These data suggest that upon E2-treatment ERα is transcriptionally activated only in female cells. In contrast, ERβ-up-regulated collagen I and III mRNA levels in cardiac fibroblasts from male rat. Thus we document for the first time a sex-specific regulation of both ER by E2 in cardiovascular cells. It may contribute to sex differences in collagen expression and cardiac fibrosis in the human heart.
