Department of Molecular, Cellular, and Developmental Biology and Biofrontiers Institute, University of Colorado, 3415 Colorado Avenue, Boulder, CO 80309-0347, USA.
Endocrinology. 2012 Sep;153(9):4480-90. doi: 10.1210/en.2012-1353. Epub 2012 Jul 3.
The incidence of cardiac hypertrophy, an established risk factor for heart failure, is generally lower in women compared with men, but this advantage is lost after menopause. Although it is widely believed that estrogens are cardioprotective, there are contradictory reports, including increased cardiac events in postmenopausal women receiving estrogens and enhanced cardiac protection from ischemic injury in female mice without estrogens. We exposed aromatase knockout (ArKO) mice, which produce no estrogens, to both pathologic and physiologic stimuli. This model allows an investigation into the effects of a complete, chronic lack of estrogens in male and female hearts. At baseline, female ArKO mice had normal-sized hearts but decreased cardiac function and paradoxically increased phosphorylation of many progrowth kinases. When challenged with the pathological stimulus, isoproterenol, ArKO females developed 2-fold more hypertrophy than wild-type females. In contrast, exercise-induced physiological hypertrophy was unaffected by the absence of estrogens in either sex, although running performance was blunted in ArKO females. Thus, loss of estrogen signaling in females, but not males, impairs cardiac function and sensitizes the heart to pathological insults through up-regulation of multiple hypertrophic pathways. These findings provide insight into the apparent loss of cardioprotection after menopause and suggest that caution is warranted in the long-term use of aromatase inhibitors in the setting of breast cancer prevention.
心肌肥厚的发生率一般女性低于男性，是心力衰竭的一个既定危险因素，但这种优势在绝经后消失。虽然人们普遍认为雌激素具有心脏保护作用，但也有相互矛盾的报告，包括绝经后接受雌激素治疗的女性心脏事件增加，以及缺乏雌激素的雌性小鼠对缺血性损伤的心脏保护增强。我们使芳香酶敲除（ArKO）小鼠暴露于病理性和生理性刺激下，该模型可研究男性和女性心脏中完全、慢性缺乏雌激素的影响。在基线时，雌性 ArKO 小鼠的心脏大小正常，但心脏功能下降，许多促生长激酶的磷酸化水平异常升高。当受到异丙肾上腺素这一病理性刺激时，ArKO 雌性小鼠发生的心肌肥厚是野生型雌性小鼠的 2 倍。相比之下，雌激素缺乏对两性的运动诱导的生理性心肌肥厚没有影响，尽管 ArKO 雌性小鼠的跑步表现受损。因此，雌激素信号在雌性而非雄性中的缺失会损害心脏功能，并通过多条肥厚途径的上调使心脏对病理性刺激敏感。这些发现为绝经后心脏保护作用明显丧失提供了深入了解，并提示在乳腺癌预防中使用芳香酶抑制剂时需要谨慎长期使用。
