脂滴表面蛋白Plin5在压力负荷性心肌重构中的作用及机制研究

Myocardial remodeling, one of the pathogenesis of heart failure, plays a crucial role in the development of heart failure. As one of organs with active lipid metabolism, most of the cardiac energy supply is derived from fatty acid oxidation., while the abnormal lipid metabolism is associated with the cardiac remodeling and heart failure. As an important lipid droplet protein, Plin5 is highly expressed in the organs with active lipid metabolism, such as heart and liver, but its roles in the development of diseases are yet unknown. Our previous studies have shown that the lipolysis and fatty acid oxidation were elevated significantly by Plin5 deficiency in liver, resulting in hepatic lipotoxic injury, which is a vital factor in the process of myocardial remodeling during heart failure. Moreover, we have also found that Plin5 deficiency promotes the production of reactive oxygen species (ROS) in cardiomyocytes, and deteriorates the development of heart failure. Based on the previous results, using Plin5-null mice with transverse aortic constriction (TAC), this study is designed to further investigate the effects of Plin5 deficiency on pressure overload-induced myocardial remodeling, and the alterations of lipid metabolism and lipotoxic injury in myocardial cells during this process. The possible mechanism of Plin5 underlying pressure overload-induced myocardial remodeling will be discussed through the analysis of effects of Plin5 deficiency on key regulatory signaling pathways involved in the process of heart failure. This study could provide experimental data for understanding the roles of Plin5 in cardiac lipid metabolism, and contribute to the basic foundation for studies on prevention and treatment of pressure overload-induced myocardial remodeling and heart failure.

心肌重构是心衰发生发展的决定性过程。作为脂肪代谢活跃器官，心脏的能量供应主要来自脂肪酸氧化，但脂肪代谢异常与心肌重构和心衰发生密切相关。脂滴蛋白Plin5在心脏和肝脏等组织中高表达，其与疾病发生之间的关系目前尚不清楚。我们研究发现，Plin5缺失能够加快肝细胞脂滴水解和脂肪酸氧化，诱发脂毒性损伤。同时，我们发现在小鼠主动脉缩窄术（TAC）模型中，Plin5缺失增加心肌ROS水平，且心衰进程也明显加快，但具体机制尚不清楚。本研究已有的工作基础上，利用Plin5敲除小鼠TAC模型，研究Plin5缺失对压力负荷心肌重构和心衰发生的影响，以及在此过程中心肌细胞脂肪代谢和脂毒性损伤的变化。最后通过分析Plin5缺失对心肌重构和代谢关键调控信号通路的影响，阐明Plin5在此过程中的作用机制。本研究结果不仅有助于认识Plin5在心脏脂肪代谢调控中的作用，也为压力负荷性心肌重构和心衰的防治提供研究基础。

心肌重构是心衰发生发展的决定性过程。作为脂肪代谢活跃器官，心脏的能量供应主要来自脂肪酸氧化，但脂肪代谢异常与心肌重构和心衰发生密切相关。脂滴蛋白Plin5在心脏和肝脏等组织中高表达，其与疾病发生之间的关系目前尚不清楚。本研究在野生小鼠和plin5敲除小鼠上构建了主动脉缩窄术（TAC）模型，结果发现，Plin5缺失加重了TAC模型诱导的心肌肥大，恶化了TAC诱导的心肌功能紊乱。Plin5缺失还激活TAC处理心肌细胞线粒体增殖，加重TAC诱导的心肌氧化应激。进一步研究发现，Plin5缺失能够激活TAC处理心肌细胞中PPARα信号。为了进一步明确这一发现，我们利用H9C2细胞模拟成体心肌细胞，结果发现，Plin5的KD能够降低脂质储积，升高脂肪酸氧化，增加氧化应激，也进一步激活了PPARα信号通路。这些结果说明，Plin5缺失降低了心肌细胞脂质积累，促进脂肪酸氧化，激活PPARα，促进线粒体增殖，从而促进脂解。这个过程引起大量的ROS产生，进一步加重TAC手术造成的心衰。本研究结果不仅有助于认识Plin5在心脏脂肪代谢调控中的作用，也为压力负荷性心肌重构和心衰的防治提供研究基础。