心肌应激性衰老通过SASP调控炎性微环境影响急性心梗后心肌重构

Acute myocardial infarction (AMI) is an emergency and severe disease with high disability and fatality. The mortality of complications induced by cardiac remodeling, such as ventricular aneurysm, heart failure and cardiac rupture, keeps staying high for years. Medical field has been continuously searching for the effective targets against cardiac remodeling to save more lives. Our previous study has revealed that stress-induced senescence exists in the myocardium after AMI, which can be inhibited significantly by ALDH2 activation. ALDH2 has been found to possess the anti-aging ability. There are complex mechanisms exerting the regulatory effects on cellular senescence. Hence, regarding ALDH2 as a cutting point for subsequent research may be a fast and efficient solution to explore the role and mechanisms of myocardial senescence in cardiac remodeling after AMI. We will examine the level of senescence-like phenotypes and inflammatory factors in the myocardium, as well as evaluate the extent of cardiac remodeling after AMI in ALDH2 transgenic mice. Then, through using the technology of two-dimensional electrophoresis and mass spectrometry analysis, the differently expressed proteins will be identified. Further, the regulatory network responsible for the myocardial aging can be constructed, by the methods of gene overexpressing or silencing, pull-down, co-immunoprecipitation and other assays. Eventually, the critical molecular targets involved in myocardial senescence will be determined, which may help develop novel strategies for prevention and treatment of cardiac remodeling after AMI.

急性心肌梗死（AMI）是一种致残率和致死率均极高的心血管急危重症，并且多年来由于AMI后心肌重构引起的室壁瘤形成、心力衰竭及心脏破裂等并发症所致死亡率持续居高不下。因此，探寻防治AMI后心肌重构的有效干预靶点一直是医学界的研究热点。我们前期研究发现，AMI后心肌存在应激性衰老现象，且激活ALDH2可抑制这一病理变化，但心肌衰老在AMI后心肌重构中的作用地位及机制仍不明确。故本项目拟以ALDH2为切入点，通过观察ALDH2转基因小鼠AMI模型中心肌细胞衰老表型、SASP炎性因子和心肌重构指标的变化，快速有效地评估心肌应激性衰老的病理角色；通过二维电泳-质谱分析寻找差异表达蛋白，确定参与心肌衰老的主要信号分子；通过基因过表达/RNA干扰、pull-down、co-IP等技术，构建调控细胞衰老的信号网络并明确关键靶点，以期探索抑制AMI后心肌重构、改善预后的新机制和防治的新策略。

急性心肌梗死（AMI）是一种致残率和致死率均极高的心血管急危重症，并且多年来由于AMI后心脏重构引起的室壁瘤形成、心力衰竭及心脏破裂等并发症所致死亡率持续居高不下。因此，探寻防治AMI后心脏重构的有效干预靶点一直是医学界的研究热点。干预心肌细胞命运以抑制心脏重构，是防治心力衰竭和改善预后的有效策略。心肌细胞在肥胖、化疗药和压力性负荷、缺氧等刺激条件下可发生应激性衰老现象，但直至该项目立项为止，这种细胞命运是否在AMI后心脏重构中发挥作用仍不清楚。项目结果表明，梗死后的小鼠心脏和缺血的人心肌组织均显示衰老标志物增加。并且，小鼠急性心肌梗死后，衰老心肌细胞分泌CCN家族成员1（CCN1）、白细胞介素-1α、肿瘤坏死因子α和单核细胞趋化蛋白-1等多种衰老相关分泌表型因子。在此基础上，我们发现了调控心肌细胞衰老的关键分子GATA4，并通过系列动物和细胞实验明确了心肌细胞衰老影响急性心梗后心肌重构的分子机制与GATA4调控的CCN1分泌有关。基于上述结果，本研究必将对改善心梗后预后、降低病死率，具有重要意义。