Effects of Estrogen, an ERα Agonist and Raloxifene on Pressure Overload Induced Cardiac Hypertrophy

Abstract

The aim of this study was to investigate the effects of 17β-estradiol (E2), the selective ERα agonist 16α-LE2, and the selective estrogen receptor modulator (SERM) raloxifene on remodeling processes during the development of myocardial hypertrophy (MH) in a mouse model of pressure overload. Myocardial hypertrophy in ovariectomized female C57Bl/6J mice was induced by transverse aortic constriction (TAC). Two weeks after TAC, placebo treated mice developed left ventricular hypertrophy and mild systolic dysfunction. Estrogen treatment, but not 16α-LE2 or raloxifene reduced TAC induced MH compared to placebo. E2, 16α-LE2 and raloxifene supported maintenance of cardiac function in comparison with placebo. Nine weeks after induction of pressure overload, MH was present in all TAC groups, most pronounced in the raloxifene treated group. Ejection fraction (EF) was decreased in all animals. However, 16α-LE2 treated animals showed a smaller reduction of EF than animals treated with placebo. E2 and 16α-LE2, but not raloxifene diminished the development of fibrosis and reduced the TGFβ and CTGF gene expression. Treatment with E2 or 16α-LE2 but not with raloxifene reduced survival rate after TAC significantly in comparison with placebo treatment. In conclusion, E2 and 16α-LE2 slowed down the progression of MH and reduced systolic dysfunction after nine weeks of pressure overload. Raloxifene did not reduce MH but improved cardiac function two weeks after TAC. However, raloxifene was not able to maintain EF in the long term period.

Cardiomyocyte-specific Estrogen Receptor Alpha Increases Angiogenesis,Lymphangiogenesis and Reduces Fibrosis in the Female Mouse Heart Post-Myocardial Infarction

“…In our study, although both female and male ERα-OE mice displayed increased angiogenesis and lymphangiogenesis, only female ERα-OE mice exhibited significantly reduced expression of Col I and III mRNA and less cardiac fibrosis after MI. These data are further supported by our recent study showing that ERα is significantly involved in the inhibition of cardiac fibrosis in female mice [68]. The increased angiogenesis/lymphangiogenesis and attenuated fibrosis in female ERα-OE mice following MI could be one explanation for the phenomenon that hearts of female ERα-OE mice did not exhibit accelerated or adverse post-infarct remodelling, indicated by maintained systolic and diastolic volumes and LV wall thickness after MI.…”

Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis

“…The functional roles of ERα in the heart are not consistent. While the activation of ERα by its agonist attenuates cardiac hypertrophy and improves heart function in TAC, spontaneous hypertensive, and DOCA animal models [36,39,40], ERα KO mice develop cardiac hypertrophy after TAC to the same extent as that in WT littermate [38]. More studies are needed to determine the exact roles of the individual estrogen receptors and their interactions in response to various stresses in the female versus the male heart.…”

Responsiveness of Brca1 and Trp53 Deficiency–Induced Mammary Preneoplasia to Selective Estrogen Modulators versus an Aromatase Inhibitor in Mus musculus

“…Observation groups (Ob) were aged to 12m for appearance of tumor. Treatment/control groups were aged to 4m for tamoxifen (T) (25mg/60d/subcutaneous pellet_12.99 mg/kg/day, Innovative Research of America, Sarasota, Florida) (13,15), raloxifene (R) (22.5mg/60d/subcutaneous pellet_11.44 mg/kg/day, Innovative Research of America) (33,34), letrozole (L) (2.5mg/60d/subcutaneous pellet_1.29 mg/kg/day, Innovative Research of America) (15), placebo pellet (P) (Innovative Research of America, Sarasota, Florida) or sham surgery (S). Initial group size determined from previous experiments (5,13,14) to ensure n≥10 at observation/treatment endpoints.…”