心肌肥大是指以心肌细胞体积增大为特征的重塑过程，发生机制不清。硫化氢（H2S）水平在心肌肥大的机体内明显下降，外源性补充H2S可抑制多种类型的心肌肥大，但确切机制均未完全阐明。KLF5作为一种基本的转录因子在心肌肥大中发挥着重要的作用。我们的预实验结果提示，H2S可阻止AngII诱导乳大鼠心肌细胞肥大过程中KLF5的表达增加，降低KLF5和心肌肥大基因ANF启动子的活性，提示KLF5可能作为一个重要的分子靶点，在H2S调节心肌肥大过程中发挥关键作用。因此，本项目拟从离体细胞和整体动物水平验证科学假说：H2S可影响反式作用因子与KLF5启动子区的结合，在转录水平调控KLF5的表达，或对KLF5产生某种形式的蛋白修饰，进而影响ANF的表达，发挥抗心肌肥大作用，从而揭示H2S调节心肌肥大的新机制，为H2S对心肌肥大的治疗提供更明确的生物学靶点，具有重要的理论价值和潜在的应用前景。

Myocardial hypertrophy is a remodeling process characterized by increased volumes of cardiomyocytes. Its mechanism is not completely understood. Level of hydrogen sulfide (H2S) decreased significantly in body suffering from myocardial hypertrophy, and exogenously H2S supply can inhibit several kinds of myocardial hypertrophy, but the detailed mechanism has not been known very well. KLF5, as a basic transcription factor, plays an important role in myocardial hypertrophy. Our preliminary experiments have showed that H2S attenuated up-regulation of KLF5 expression in cardiomyocyte hypertrophy induced by Ang II, decreased the activity of KLF5 and ANF promoter, which suggest that KLF5 may be a vital molecular target in the process of regulation myocardial hypertrophy by H2S. Furthermore, the project in vivo and in vitro is to validate the hypothesis that H2S may influence transacting factor binding to promoter of KLF5, then regulate KLF5 expression in transcriptional level. H2S may also modify structures of KLF5 protein to inhibit ANF expression and myocardial hypertrophy. It may be a novel mechanism on regulating myocardial hypertrophy by H2S and provide more unambiguous therapeutic targets for treatment of myocardial hypertrophy, which may show important theoretical value and potential application prospect.

心肌肥大是心肌缺血、心肌梗死、心力衰竭等多种心血管疾病的独立危险因素。硫化氢（H2S）作为一种气体信号分子，参与机体多种病理生理学过程，外源性补充H2S可抑制多种类型心肌肥大，但其具体机制不清。本课题从人体临床样本、心肌肥大动物模型和离体血管紧张素II（Ang II） 诱导心肌肥大细胞模型，探讨H2S对心肌肥大影响及Krüppel样因子5（KLF5）和去乙酰化酶3（SIRT3）在其中的关键调控作用。结果发现临床心肌肥厚患者的心脏组织中CSE水平明显降低，而KLF5表达增加；外源性补充H2S有助于恢复H2S/CSE系统的平衡，通过巯基硫化修饰特异性蛋白1（SP-1）的半胱氨酸664位点来调控KLF5转录活性，降低SP-1与KLF5启动子的结合，下调KLF5的启动子活性、mRNA和蛋白水平，并可抑制KLF5向血小板源性生长因子（PDGF-A）的招募及降低PDGF-A启动子活性，进而改善心肌肥厚的心脏构型，减少心肌细胞面积，下调肥大基因ANP水平。此外H2S也可通过增加SIRT3的启动子活性和蛋白表达，改善心肌线粒体结构、维持线粒体的分裂和融合的动态平衡，改善线粒体功能，上调抗氧化蛋白表达，减轻氧化应激水平，进而改善心肌肥厚的心脏构型，减少心肌细胞面积，下调肥大基因ANP、BNP和β-MHC水平。该项研究为心肌肥厚的治疗提供更有效的药物靶点和治疗前景，具有崭新的理论价值和潜在的应用价值。