Androgens in cardiac hypertrophy

在高血压心血管疾病中，雌激素和雄激素具有重要的病理生理作用。虽然雌激素似乎主要是保护性的，但雄激素的作用还没有明确的定义。雄激素可通过不同途径诱导或加重高血压和心肌肥厚。然而，雄激素对心血管的有益作用也已被描述。雄激素除了通过经典的雄激素受体(AR)调节靶基因的转录活性外，还在包括心肌细胞和血管内皮细胞在内的多种细胞类型中发挥快速的非基因组效应。这些作用包括细胞内钙离子的增加、ERK1/2、Akt等激酶的激活、mTOR的磷酸化以及离子通道的调节。除了AR的基因组作用外，雄激素的快速作用可能是心肌肥厚发展过程中性别差异的原因之一。关于负责受体和AR参与快速作用的结果是不一致的。不同组织中的中介蛋白可能是不同的。由于这些分子机制尚不清楚，快速雄激素作用的潜在治疗意义仍未被探索。我们小组将进一步分析在第一个资助期产生的AR在心肌细胞和内皮细胞中表达改变的新动物模型，并使用它们以及合适的细胞培养模型来阐明心脏中快速雄激素信号传递的分子机制和生理和病理生理功能。

In hypertensive cardiovascular diseases, estrogens and androgens have important pathophysiological effects. While estrogens seem to be mainly protective, the role of androgens is not yet well-defined. Androgens may induce or worsen hypertension and cardiac hypertrophy by different pathways. However, beneficial cardiovascular effects of androgens have also been described. Besides their well-known actions on the transcriptional activity of target genes mediated by the “classical” androgen receptor (AR), androgens also exert rapid, non-genomic effects in numerous cell types including cardiomyocytes and endothelial cells. These effects involve increases in intracellular calcium, activation of kinases such as ERK1/2, Akt, phosphorylation of mTOR, as well as the modulation of ion channels. Besides the genomic actions by the AR, the rapid effects of androgens may be a reason for sex differences in the development of myocardial hypertrophy. Results concerning the responsible receptors and the involvement of AR in the rapid actions are inconsistent. The mediating proteins are possibly different in different tissues. Since these molecular mechanisms are not yet well understood, potential therapeutic implications of the rapid androgen actions remained unexplored. Our group will further phenotypically analyse the new animal models generated in the first funding period with altered expression of AR in cardiomyocytes and endothelial cells and use them as well as suitable cell culture models to clarify the molecular mechanisms and the physiological and pathophysiological functions of rapid androgen signalling in the heart.