甲基转移酶SUV39H1调控病理性心肌肥大/心力衰竭的机制研究

心力衰竭（HF）是近年来发病率增长速度最快的一类心血管疾病。众多心衰致病因素引起心衰的机制不尽相同，但在初期都会诱导病理性的心肌肥大。我们前期研究发现，组蛋白甲基转移酶SUV39H1在病理性心肌肥大小鼠模型心脏中表达上调。血管紧张素II处理原代心肌细胞或原代心肌成纤维细胞上调SUV39H1表达。在小鼠中系统性敲除SUV39H1或系统性抑制SUV39H1活性显著抑制病理性心肌肥大、心肌纤维化、改善心功能并降低因心衰导致的死亡率。以上预实验结果提示，SUV39H1可能参与病理性肥大/心衰的发生发展。我们拟在此基础上利用动物实验、细胞与分子生物学实验结合转录组/表观遗传组学技术进一步研究SUV39H1如何通过改变心肌细胞、心肌成纤维细胞中的基因表达谱、促进病理性肥大/心衰的表观遗传机制，从而为临床治疗心力衰竭提供理论依据及药物靶标。

Heart failure represents a group of cardiovascular diseases that have emerged as one of the fast growing subsets in the past decade. Different etiological factors, though through distinct pathways, invariably lead to heart failure via the induction of pathological hypertrophy. We preliminary data indicate that expression of SUV39H1, the mammalian histone H3K9 trimethyltransferase, is up-regulated in the heart in mice induced to develop pathological hypertrophy by either angiotensin II (Ang II) infusion or transverse aortic constriction. Ang II stimulation up-regulates the expression of SUV39H1 in primary rat cardiomyocytes and cardiac fibroblast cells. On the contrary, systemic deletion of SUV39H1 or inhibition of SUV39H1 activity in mice alleviates pathological hypertrophy, attenuates cardiac fibrosis, and improves heart function that collectively ameliorate survival rate. Based on these data, we propose that SUV39H1 might play a significant role promoting the pathogenesis of cardiac hypertrophy and heart failure. We plan to investigate, using a combination of animal models, cell and molecular biology experiments, as well as transcriptomic/epigenomic techniques, the epigenetic mechanism whereby SUV39H1 contributes to pathological hypertrophy and heart failure. We goal is to provide a clear rationale to exploit SUV39H1 as a druggable target in the treatment of cardiac hypertrophy and heart failure.