Cardiac Phenomics Laboratory, Department of Physiology, University of Melbourne, Victoria 3010, Australia.
Endocrinology. 2011 Dec;152(12):4937-47. doi: 10.1210/en.2011-1212. Epub 2011 Oct 25.
The conventional view is that estrogen confers female cardioprotection. Estrogen synthesis depends on androgen availability, with aromatase regulating conversion of testosterone to estradiol. Extragonadal aromatase expression mediates estrogen production in some tissues, but a role for local steroid conversion has not yet been demonstrated in the heart. This study's goal was to investigate how aromatase deficiency influences myocardial function and ischemic resilience. RT-PCR analysis of C57Bl/6 mouse hearts confirmed cardiac-specific aromatase expression in adult females. Functional performance of isolated hearts from female aromatase knockout (ArKO) and aromatase wild-type mice were compared. Left ventricular developed pressures were similar in aerobic perfusion, but the maximal rate of rise of ventricular pressure was modestly reduced in ArKO hearts (3725 ± 144 vs. 4272 ± 154 mm Hg/sec, P < 0.05). After 25 min of ischemia, the recovery of left ventricular developed pressure was substantially improved in ArKO (percentage of basal at 60 min of reperfusion, 62 ± 8 vs. 30 ± 6%; P < 0.05). Hypercontracture was attenuated (end diastolic pressure, 25 ± 5 vs. 51 ± 1 mm Hg; P < 0.05), and lactate dehydrogenase content of coronary effluent was reduced throughout reperfusion in ArKO hearts. This was associated with a hyperphosphorylation of phospholamban and a reduction in phosphorylated Akt. Immediately after reperfusion, ArKO hearts exhibited increased incidence of ventricular premature beats (194 ± 70 vs. 46 ± 6, P < 0.05). These observations indicate more robust functional recovery, reduced cellular injury, and modified cardiomyocyte Ca(2+) handling in aromatase-deficient hearts. Our findings indicate that androgen-to-estrogen conversion may be of pathophysiologic importance to the heart and challenge the notion that estrogen deficiency is deleterious. These studies suggest the possibility that aromatase suppression may offer inotropic benefit in the acute ischemia/reperfusion setting with appropriate arrhythmia management.
传统观点认为雌激素赋予女性心脏保护作用。雌激素的合成依赖于雄激素的可用性，而芳香酶则调节睾酮转化为雌二醇。外源性芳香酶在某些组织中介导雌激素的产生，但局部类固醇转化在心脏中的作用尚未得到证实。本研究旨在探讨芳香酶缺乏如何影响心肌功能和耐缺血能力。C57Bl/6 小鼠心脏的 RT-PCR 分析证实了成年雌性心脏中存在特异性芳香酶表达。比较了雌性芳香酶敲除（ArKO）和野生型小鼠分离心脏的功能表现。有氧灌注时左心室发展压相似，但 ArKO 心脏的心室压力最大上升率略有降低（3725±144 与 4272±154mmHg/sec，P<0.05）。缺血 25 分钟后，ArKO 左心室发展压的恢复明显改善（再灌注 60 分钟时的基础百分比，62±8%与 30±6%；P<0.05）。过度收缩减弱（舒张末期压，25±5 与 51±1mmHg；P<0.05），并且 ArKO 心脏在整个再灌注期间冠状动脉流出液中的乳酸脱氢酶含量减少。这与磷蛋白磷酸化增加和磷酸化 Akt 减少有关。再灌注后立即，ArKO 心脏出现更多的室性早搏（194±70 与 46±6，P<0.05）。这些观察结果表明，芳香酶缺乏的心脏具有更强的功能恢复、减少的细胞损伤和改变的心肌细胞 Ca(2+)处理。我们的发现表明，雄激素向雌激素的转化可能对心脏具有病理生理重要性，并挑战了雌激素缺乏有害的观点。这些研究表明，在适当的心律失常管理下，芳香酶抑制可能在急性缺血/再灌注情况下提供正性肌力作用。
