Institute of Gender in Medicine, Charité-Medical University Berlin, Germany.
Am J Physiol Regul Integr Comp Physiol. 2010 Jun;298(6):R1597-606. doi: 10.1152/ajpregu.00825.2009. Epub 2010 Apr 7.
We investigated sex differences and the role of estrogen receptor-beta (ERbeta) on myocardial hypertrophy in a mouse model of pressure overload. We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ERbeta knockout (ERbeta(-/-)) mice. All mice were characterized by echocardiography and hemodynamic measurements and were killed 9 wk after surgery. Left ventricular (LV) samples were analyzed by microarray profiling, real-time RT-PCR, and histology. After 9 wk, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. ERbeta deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that WT male hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than WT female hearts. ERbeta(-/-) mice exhibited a different transcriptional response. ERbeta(-/-)/TAC mice of both sexes exhibited induction of proapoptotic genes with a stronger expression in ERbeta(-/-) males. Cardiac fibrosis was more pronounced in male WT/TAC than in female mice. This difference was abolished in ERbeta(-/-) mice. The number of apoptotic nuclei was increased in both sexes of ERbeta(-/-)/TAC mice, most prominent in males. Female sex offers protection against ventricular chamber dilation in the TAC model. Both female sex and ERbeta attenuate the development of fibrosis and apoptosis, thus slowing the progression to heart failure.
我们研究了性别差异以及雌激素受体-β（ERβ）在压力超负荷小鼠模型中心肌肥厚中的作用。我们对雄性和雌性野生型（WT）和 ERβ敲除（ERβ（-/-））小鼠进行了横主动脉缩窄（TAC）或假手术。所有小鼠均通过超声心动图和血流动力学测量进行了特征描述，并在手术后 9 周时处死。通过微阵列分析、实时 RT-PCR 和组织学分析对左心室（LV）样本进行了分析。9 周后，WT 雄性比 WT 雌性表现出更多的肥大和心力衰竭迹象。值得注意的是，WT 雌性发展为同心性肥大，而雄性发展为离心性肥大。ERβ缺失增强了两种性别 TAC 诱导的心肌细胞直径增加。基因表达谱分析显示，WT 雄性心脏比 WT 雌性心脏更强地诱导基质相关基因的表达，更强地抑制线粒体基因的表达。ERβ（-/-）小鼠表现出不同的转录反应。两种性别 ERβ（-/-）/TAC 小鼠均诱导促凋亡基因的表达，而 ERβ（-/-）雄性中的表达更强。与雌性小鼠相比，WT/TAC 雄性的心肌纤维化更为明显。在 ERβ（-/-）小鼠中，这种差异被消除。两种性别 ERβ（-/-）/TAC 小鼠的凋亡核数量均增加，雄性更为明显。雌性性别为 TAC 模型中的心室腔扩张提供了保护。雌性性别和 ERβ 均可减轻纤维化和细胞凋亡的发展，从而减缓向心力衰竭的进展。
