组蛋白甲基转移酶Suv420h1通过甲基化H4K20和ERK1调节心肌肥厚

Cardiac hypertrophy is an important risk factor of heart failure, and its pathological mechanisms have not been yet fully elucidated. Previously researches demonstrated that histone methylation is the important means to regulate cardiac hypertrophy. Suv420h1 is a kind of histone methyltransferases, but the role and mechanism of Suv420h1 on cardiac hypertrophy remain unclear. Therefore, experiments consist of four parts are designed in this research proposal to unravel the role and mechanism of Suv420h1 on cardiac hypertrophy. Firstly, we will detect the expression levels of Suv420h1 in the hearts of wild-type mice with or without transverse aortic constriction (TAC) or in the cultured neonatal rat cardiomyocytes (NRCMs) treated with or without angiotensin II (Ang II) for indicated times. Secondly, we will generate AdshSuv420h1 and AdSuv420h1 adenoviruses to infect the NRCMs, after that, these cells will be treated with Ang II to induce hypertrophy to investigate the role and mechanism of Suv420h1 on cardiomyocytes hypertrophy. Thirdly, the mice with cardiac-specific deletion or overexpression of Suv420h1 were subjected to TAC or Sham surgery to ascertain the function and mechanism of Suv420h1 on cardiac hypertrophy in vivo. Finally, the expression levels of Suv420h1 in the hearts of hypertrophic cardiomyopathy or dilated cardiomyopathy will be detected. This proposal tries to provide prevention and therapeutic target for cardiac hypertrophy.

心肌肥厚是导致心力衰竭的重要危险因素,但其发生机制尚未完全阐明。研究表明组蛋白甲基化是调节心肌肥厚的重要方式，Suv420h1是一种组蛋白甲基转移酶，但其对心肌肥厚的影响及机制尚未见报道。因此，本项目拟通过四部分实验阐明Suv420h1对心肌肥厚的影响及其机制，首先拟检测Suv420h1在心肌肥厚小鼠及肥大的心肌细胞中的表达水平；然后通过构建Suv420h1过表达和沉默腺病毒，并分别感染原代大鼠心肌细胞，Ang II刺激建立体外心肌细胞肥大模型，明确Suv420h1对心肌细胞肥大的影响及其机制；再通过主动脉缩窄术建立小鼠心肌肥厚模型，阐明Suv420h1基因敲除或过表达后对小鼠心肌肥厚的影响及机制；最后拟通过检测人类肥厚型心肌病和扩张型心肌病患者心脏组织中Suv420h1的表达水平，以期能为临床防治心肌肥厚提供新靶点。

心血管疾病是我国面临的重大公共卫生问题，是危害居民生命健康的“第一杀手”，心脏重构是导致多种心血管疾病的独立危险因素，因此，阐明心脏重构的病理生理机制对预防和治疗心血管疾病具有重要意义。组蛋白甲基转移酶是一类具有蛋白质甲基转移酶活性的酶类，不仅能甲基化组蛋白，也能甲基化非组蛋白。目前发现的蛋白质甲基化修饰主要发生在赖氨酸和精氨酸残基上，本项目研究的核心分子Suv420h1是一种赖氨酸特异性的甲基转移酶，其能特异性的导致组蛋白H4第20位赖氨酸的二或三甲基化（H4K20me2/3），也有文献报道其能甲基化非组蛋白，如ERK1的第302位和361位赖氨酸，从而影响ERK1的磷酸化水平，促进肿瘤的发生。本项目从分子、细胞以及动物水平系统阐明了Suv420h1对心肌肥厚的调控作用及分子机制。首先，我们研究结果发现与正常供体心脏比较，扩心病病人中Suv420h1的蛋白表达水平显著降低，提示其可能与扩心病病人的心脏重构相关，进一步的研究发现，干扰素调节因子6（IRF6）过表达后显著抑制Suv420h1的表达水平。其次，我们通过构建了Suv420h1敲低和过表达的慢病毒质粒，分别感染大鼠原代心肌细胞，结果显示，Suv420h1敲低显著促进Ang II诱导的心肌细胞肥大，而Suv420h1过表达则显著抑制心肌细胞肥大。第三，我们引进了Suv420h1的条件性敲除小鼠，通过与Myh6-Cre杂交获得了心肌细胞特异性敲除Suv420h1的小鼠（Suv420h1-cKO）,结果显示，Suv420h1敲除后显著促进压力负荷诱导的心肌肥厚。第四，进一步的机制研究发现，Suv420h1能与HDAC1相互作用，而并不能与HDAC3相互作用，提示HDAC1可能介导了Suv420h1对心肌肥厚的调控作用。本项目的研究成果明确了Suv420h1对心肌肥厚的调控作用和机制，并建立了蛋白质甲基化与乙酰化之间的Cross-talk，同时目前Suv420h1以及HDAC具有相关的抑制剂，具有较大的临床应用潜力。

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