FOR 1054: Sex-Specific Mechanisms in Myocardial Hypertrophy

心血管疾病是全世界男性和女性最常见的死亡原因。然而，男性在较早的年龄就会患上大多数(但不是全部)心血管疾病，而女性在侵入性治疗中风险更大。心力衰竭(HF)是一种对心肌肥厚(MH)的不良适应，是心血管死亡的常见原因。男性和女性的适应能力是不同的。了解这些差异可能会导致对男性和女性都有利的新疗法。该研究组的主要目的是调查男男性接触者和心力衰竭患者中女性的保护作用。当承受压力或容量超负荷时，女性心脏比男性心脏发展出更有利的心肌重塑的生理形式。我们假设，女性心脏更有利的重塑涉及几个基于细胞的保护通路的协同活性，这些通路是由雌激素信号通过雌激素受体诱导的，从而影响线粒体功能和心肌能量代谢。我们推测，相反，睾酮通过雄激素受体诱导基质重塑和生长因子信号传递，并有助于偏心重塑，特别是在男性。我们计划对线粒体功能、蛋白激酶B(AKT)相关信号、脂肪酸和花生四烯酸相关代谢以及基质合成方面的性别差异进行一系列相互关联的机制研究。生理性和病理性MH和HF的动物模型，结合细胞特异性和/或诱导的激素受体基因缺失或过度表达，将被用于分析与激素相关的和基于染色体的性别差异。雌激素和雄激素受体(ER和AR)的作用及其与肥大信号的相互作用将被具体分析。同时，我们将比较应激诱导的女性和男性心肌转录组和蛋白质组的变化，以检测新的性别特异性途径。我们将测试新的药理学方法，以检测性别特异性的影响。最后，我们将研究在动物模型中观察到的机制是否可以应用于人类心脏。一项关于人类主动脉狭窄患者性别差异的临床研究与我们的项目相关，并将促进我们的假设检验。我们的研究虽然是基础的，但可以通过建议临床方案直接为以患者为导向的研究做出贡献。通过这种方式，我们认为我们的研究本质上是翻译的。

Cardiovascular disease is the most common cause of death in men and women worldwide. Nevertheless, men develop most, but not all, cardiovascular diseases at an earlier age, while women have greater risks during invasive therapies. Heart failure (HF), a mal-adaptation to myocardial hypertrophy (MH), is a common cause of cardiovascular death. The adaptations in men and women are different. Understanding these differences could result in novel therapies that would benefit both men and women. The primary aim of this Research Unit is to investigate the protective effect of female sex in MH and HF. Female hearts develop a more favorable physiological form of myocardial remodelling when subjected to pressure or volume overload than male hearts. We hypothesise that the more favorable remodelling in female hearts involves the synergistic activity of several cellular-based protective pathways induced by estrogen signalling via estrogen receptors, thereby influencing mitochondrial function and myocardial energy metabolism. We speculate that, in contrast, testosterone induces matrix remodelling and growth factor signalling via androgen receptors and contributes to eccentric remodelling, especially in males. We plan a series of inter-related mechanistic studies into sex differences in mitochondrial function, protein kinase B (AKT)-related signalling, fatty acid and arachidonic acid-related metabolism and matrix synthesis. Animal models for physiological and pathological MH and HF, in combination with cell-specific and/or inducible genetic deletion or over-expression of hormone receptors, will be used to analyse hormone-related and chromosome-based sex differences. The role of estrogen and androgen receptors (ER and AR) and their interaction with hypertrophic signalling will be specifically analysed. Simultaneously, we will compare stress-induced changes in the transcriptome and proteome in female and male myocardium to detect novel sex-specific pathways. We will test new pharmacological approaches for sex-specific effects. Finally, we will investigate whether or not the mechanisms observed in animal models can be applied to the human heart. A clinical study for sex differences in human aortic stenosis is associated with our project and will facilitate our hypotheses testing. Our research, albeit basic, could contribute directly to patient-oriented research by suggesting clinical protocols. In this way, we view our research as translational in nature.