心肌肥厚的新致病机制--组胺H2受体及其介导的关键信号通路研究

Myocardial hypertrophy, which is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues, is a fundamental pathologic process of many cardiovascular diseases. Neurohormones, such as angiotensin Ⅱ and catecholamines, are traditionally believed to be the critical cause factors in the development of myocardial hypertrophy. Of note, our previous results firstly proved that histamine and histamine H2 receptors also play an important role in the development of myocardial hypertrophy via activation of intracellular Ca2+ signaling pathway. However, the underlying mechanism of histamine H2 receptor-induced myocardial hypertrophy is still not fully understood. Our preliminary study shows that activation of histamine H2R of cardiomyocytes by H2R selective agonist dimaprit significantly increases the expression of p-ERK1/2, which has a tight regulatory relationship with Ca2+ signal, suggesting that ERK1/2 pathway may participate in the occurrence of histamine-induced myocardial hypertrophy. Moreover, a novel longevity gene product, SIRT1, which interacts with ERK1/2, is also generally thought to be participated in the development of myocardial hypertrophy, but the exact effects on myocardial hypertrophy is still controversial. Taken together, we hypothesize that ERK1/2-SIRT1 axis and Ca2+ signaling pathway may play an important regulatory role in the development of myocardial hypertrophy induced by activation of histamine H2 receptor. We introduce H2R-/- and SIRT1-/- mice, selective agonists and antagonists of key molecules, both in vivo and vitro to illustrate the key molecules and their exact transduction mechanism of histamine-induced myocardial hypertrophy. In this way, we will provide much more sufficient theoretical basis for the underlying mechanism of myocardial hypertrophy development and new potential pharmacological targets for the prevention and treatment of myocardial hypertrophy.

心肌肥厚是多种心血管病共同病理过程，危害严重。传统观念认为心肌肥厚由血管紧张素、儿茶酚胺等介导的信号通路引起,而我们前期研究首先发现组胺H2受体也在心肌肥厚发生发展中发挥重要作用，致病效应显著,与下游钙信号密切相关，但机制不明。预实验表明激动组胺H2受体引起ERK1/2信号显著变化，而ERK1/2对钙信号有明确调控作用，强烈提示组胺H2受体致心肌肥厚作用可能通过ERK1/2信号通路介导。研究表明SIRT1分子与心肌肥厚关系密切，但具体效应尚有争议，且SIRT1与ERK1/2信号存在相互调控。因此我们提出科学假说：激动组胺H2受体通过ERK1/2，SIRT1与Ca2+关键信号分子介导的转导通路致使心肌肥厚。本项目拟在离体与在体水平，利用基因敲除动物，关键分子特异性阻断与过表达，从正反两个方面对该假说进行研究，系统阐明组胺H2受体介导心肌肥厚的分子机制,为防治心肌肥厚提供新理论依据和治疗靶点。

心肌肥厚是多种心血管病共同病理过程，危害严重。传统观念认为心肌肥厚由血管紧张素、内皮素、儿茶酚胺等介导的信号通路引起，而我们前期研究首先发现组胺及其H2受体也在心肌肥厚发生发展中发挥重要作用，致病效应显著，但机制不明。通过体内和体外研究，我们首次证实激活组胺H2受体（Dimaprit）可以通过激活ERK1/2信号通路和抑制SIRT1信号通路诱导产生病理性心肌肥厚。反之，阻断组胺H2受体（法莫替丁）可通过激活SIRT1信号通路和抑制ERK1/2信号通路抑制主动脉弓缩窄术引起的病理性心肌肥厚以及血管紧张素II引起的心肌细胞肥大。此外，我们发现SIRT1是ERK1/2的负性调控因子。综上，我们得出以下结论：组胺通过结合H2受体，抑制SIRT1信号通路和激活ERK1/2信号，促进病理性心肌肥大和心肌纤维化，诱发病理性心肌重塑，从而在病理性心肌肥厚的发生发展中发挥关键作用。本研究阐明了组胺H2受体介导心肌肥厚的具体分子机制，为临床上防治心肌肥厚提供了新的理论依据和治疗靶点。