Estrogen Receptor Antagonism Exacerbates Cardiac Structural and Functional Remodeling in Female Rats
Milad C El Hajj, Van K Ninh, Elia C El Hajj, Jessica M Bradley, Jason D. GardnerAmerican Journal of Physiology - Heart and Circulatory Physiology2016
We have previously demonstrated the cardioprotective effects of ovarian hormones against adverse ventricular remodeling imposed by chronic volume overload. Here, we assess the estrogen receptor dependence of this cardioprotection. Four groups of female rats were studied: sham-operated (SHAM), volume overloaded (ACF), SHAM treated with estrogen receptor antagonist, ICI 182,780 (SHAM+ICI), and ACF treated with ICI. Cardiac function was assessed temporally using echocardiogram and tissue samples were collected at 5 days and 6 weeks post-surgery. All rats with volume overload had significantly increased cardiac output (96±32 ml/min for ACF and 108±11 ml/min for ACF+ICI versus 31±2 for SHAM, p<0.05). At 6 wks, volume overload induced significant left ventricular (LV) hypertrophy in both untreated and treated ACF groups. Both ACF groups developed significantly increased LV end diastolic diameter (LVEDD), indicating LV dilatation, with the ACF+ICI group having the greatest increase (340%, relative to SHAM). Ejection fraction was significantly reduced in the ACF+ICI group (23% reduction) at 6 weeks post-surgery as compared to untreated ACF (p<0.05). Interstitial collagen staining was significantly reduced by volume overload, with estrogen receptor antagonism causing greater collagen loss at both 5 days and 6 weeks post-surgery. Furthermore, volume overload induced a significant increase in LV wall stress only in rats treated with estrogen antagonist. These data indicate that estrogen receptor signaling is essential for sex hormone-dependent cardioprotection against adverse remodeling. The maintenance of myocardial extracellular matrix collagen appears to play a key role in this cardioprotection.