溶血磷脂酸抑制自噬促进心肌重构的机制研究

Myocardial autophagy activation plays an important protective role against myocardial remodeling. The serum levels of lysophosphatidic acid (LPA) is significantly increased after myocardial infarction （MI）. LPA can induce proliferation and collagen synthesis in cardiac fibroblasts through LPAR3，and our recent studies show that LPA can regulate cardiomyocyte hypertrophy through LPAR3. However, little is far known about the role and mechanism of LPA and its receptor signaling in myocardial remodeling. It has been demonstrated that LPA can inhibit starvation-induced cancer cell autophagy. And our preliminary experiments also show that LPA inhibits autophagy-related protein LC3 expression in cardiomyocyte. Therefore, we assumed that LPA might be a new signaling molecular which can cause myocardial remodeling, and inhibiting autophagy is an important mechanism for LPA and its receptor signaling in regulating myocardial remodeling”. In this study, we will explore the effect of LPA and its receptor signaling on myocardial remodeling, autophagy and cardiac function in MI rat treated with exogenous LPA or LPAR3 receptor blocker, and we reveal the effect of autophagy on LPA-mediated myocardial remodeling by using autophagy inducer. Further we clarify the molecular mechanism of LPA in inhibiting autophagy in LPA mediated cardiomyocyte hypertrophy, through the combination use of chemical drug and gene interference. This study will provide the possibility for the prevention and treatment of myocardial remodeling after MI through targeting LPA and its receptor signaling regulated autophagy.

心肌自噬激活在心梗后心肌重构中扮演重要保护作用。心肌梗死患者血清溶血磷脂酸（LPA）水平显著升高。研究显示，LPA通过LPAR3促进心脏成纤维细胞增殖和胶原合成，我们近期研究证实LPA通过LPAR3促进心肌细胞肥大。但LPA受体信号在心肌重构的作用及机制尚不清楚。文献报道，LPA可抑制饥饿的癌细胞自噬。我们预实验发现LPA抑制心肌细胞自噬蛋白LC3表达。因此，我们提出假说“LPA是促进心肌重构的新分子，抑制心肌自噬是LPA受体信号促进心肌重构的重要机制”。本课题首先在心肌梗死模型，外源性给予LPA或LPAR3受体阻断剂，探讨LPA对心肌重构、自噬及心功能的影响及受体机制，其次用药物激活自噬揭示自噬对LPA介导心肌重构的影响，并在细胞水平采用工具药和基因干扰相结合的方法，阐明LPA抑制自噬从而促进心肌细胞肥大的分子机制，为靶向LPA受体信号调节自噬从而防治心肌重构和心力衰竭提供可能性。

溶血磷脂酸（LPA）是一种内源性的生物活性分子，参与调节多种生物学功能。我们以往体外研究发现LPA可诱导心肌细胞肥大，但LPA在心肌梗死后心脏中的调节作用尚不清楚。近来研究表明自噬参与心肌肥大的调节。本研究旨在明确LPA在心梗后心脏功能和心肌重构中的作用，并确定自噬在LPA诱导的心肌肥大中的调节作用。动物实验用SD大鼠，通过结扎冠状动脉左前降支建立心肌梗死模型以及相应的假手术组，大鼠通过腹腔注射方式分别给予LPA和PBS治疗5周，观察LPA对心梗后心脏功能和心肌肥大的影响。体外实验培养H9C2心肌细胞，研究自噬在LPA诱导的心肌肥厚中的调节作用。动物实验结果发现：LPA促使大鼠心梗后心功能恶化，增加心肌肥厚并减少自噬表达。细胞实验结果显示：LPA降低LC3II/LC3I蛋白比率，增加P62蛋白表达，减少自噬小体形成，表明LPA导致H9C2心肌细胞自噬活性降低。自噬激活剂雷帕霉素减弱LPA诱导的自噬抑制和心肌肥大。信号机制研究发现mTOR抑制剂和PI3K抑制均能阻断LPA诱导的心肌细胞自噬和mTOR及其下游靶基因的磷酸化表达，表明LPA主要通过AKT/mTOR信号通路抑制H9C2心肌细胞自噬。另外，我们还发现敲低LPA3受体亦减弱LPA诱导的心肌细胞自噬，表明LPA通过激活LPA3和AKT/mTOR信号通路抑制自噬。本研究首次证明LPA在心梗后心脏功能和心肌肥大中发挥重要调节作用，并首次揭示了LPA和自噬在心肌肥厚中的关系。本课题表明靶向LPA受体信号可能成为缺血性心脏病和心肌肥厚的潜在治疗策略。

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