Estrogen receptor-β mediates male-female differences in the development of pressure overload hypertrophy

TLDR

Epidemiological evidence indicates gender differences in hypertrophy and heart disease, yet the underlying mechanisms and the role of estrogen receptor subtypes remain unclear. This study aimed to determine how estrogen receptor subtypes influence pressure overload–induced hypertrophy in mice. Researchers performed transverse aortic constriction or sham surgery on male and female wild‑type, ER‑α knockout, and ER‑β knockout mice, then measured body, heart, and lung weights two weeks later. Male mice exhibited a 64% increase in heart‑to‑body weight ratio and lung weight after TAC, whereas females showed only a 31% increase without heart failure; ER‑α knockout females behaved like wild‑type, but ER‑β knockout females had a markedly greater hypertrophic response and lower lipoprotein lipase expression, indicating ER‑β mediates the protective effect in females.

Abstract

The goal of this study was to determine the role of estrogen receptor subtypes in the development of pressure overload hypertrophy in mice. Epidemiological studies have suggested gender differences in the development of hypertrophy and heart disease, but the mechanism and the role of estrogen receptor subtypes are not established. We performed transverse aortic constriction (TAC) and sham operations in male and female wild-type (WT) mice and mice lacking functional estrogen receptor-alpha [alpha-estrogen receptor knockout (alpha-ERKO)] and mice lacking estrogen receptor-beta (beta-ERKO). Body, heart, and lung weights were measured 2 wk postsurgery. WT male mice subjected to TAC showed a 64% increase in the heart weight-to-body weight ratio (HW/BW) compared with sham, and WT males have increased lung weight at 2 wk. WT female mice subjected to TAC showed a 31% increase in HW/BW compared with sham, which was significantly less than their male counterparts and with no evidence of heart failure. alpha-ERKO females developed HW/BW nearly identical to that seen in WT littermate females in response to TAC, indicating that estrogen receptor-alpha is not essential for the attenuation of hypertrophy observed in WT females. In contrast, beta-ERKO females responded to TAC with a significantly greater increase in HW/BW than WT littermate females. beta-ERKO females have lower expression of lipoprotein lipase at baseline than WT or alpha-ERKO females. These data suggest an important role for estrogen receptor-beta in attenuating the hypertrophic response to pressure overload in females.