基于MEF2D的SUMO/去SUMO化修饰调节探讨SENP3促进病理性心肌肥大的作用及机制研究

病理性心肌肥大是慢性心力衰竭的前驱病变，该过程中发生大量关键基因的转录及蛋白翻译后修饰异常。申请人前期证实SIRT1直接去乙酰化PKC-zeta改善心肌肥大。近期研究发现SUMO特异性蛋白酶SENP3在ISO诱导的体内外心肌肥大模型中皆表达升高，过表达SENP3诱导心肌细胞肥大，免疫沉淀-质谱筛选发现，SENP3与促心肌肥大转录因子MEF2D存在直接结合。据此我们提出科学假说：SENP3可能通过直接去SUMO化修饰MEF2D，增强其转录活性介导心肌肥大的发生发展。本项目拟明确SENP3介导病理性心肌肥大的确切机制，重点研究：①SENP3是否通过调控MEF2D活性诱导心肌肥大；②探讨MEF2D的SUMO/去SUMO化修饰调节对其转录活性的调节作用及具体分子机制。通过本课题的实施，我们将揭示病理性心肌肥大的新机制，为从调控MEF2D的SUMO化修饰角度探寻抗心肌肥大的新途径提供充分的科学依据。

Pathological cardiac hypertrophy is a precursor of chronic heart failure, and this process is accompanied with abnormal post-translational modification and transcription of a large number of key genes. Our previous studies confirmed that SIRT1 improved pathological cardiac hypertrophy via directlydeacetylated PKC-zeta the balance of acetylation/deacetylation modification of substrate protein played a crucial role in the regulation of cardiac hypertrophy. Recently, our preliminary studies indicate that the expression of SUMO specific protease SENP3 was elevated in ISO induced cardiac hypertrophy and over expression of SENP3 induced cardiac hypertrophy. Moreover, the result of immunoprecipitation-mass spectrometry showed that the transcription factor MEF2D directly bound to SENP3. Based on this, we propose a scientific hypothesis: SENP3 may directly deSUMOylate MEF2D and strengthen the transcriptional activity and finally induce cardiac hypertrophy. Based on these foundations, the current project was performed to confirm the regulatory effects of SENP3 on cardiac hypertrophy and determine whether SENP3 induces cardiac hypertrophy by regulating MEF2D activity. Then, further efforts will be made to reveal the role of the balance of the SUMO/SUMOylation of MEF2D on the activity of MEF2D and explore the potential mechanism. Through the implementation of this project, we will reveal the new mechanism of cardiac hypertrophy, and the study will pave the way to the therapeutic strategies of pathological cardiac hypertrophy.