磷脂酰乙醇胺 N-甲基转移酶介导心肌细胞肥大的力学生物学机制研究

Phospholipid metabolism disorder was involved in cardiomyocyte hypertrophy induced by pressure overload, but the underlying pathological mechanism was poorly understood. Phosphatidylethanolamine (PE) decrease and phosphatidylcholine (PC) increase are the main features of phospholipid metabolism disorder in this process. phosphatidylethanolamine N-methyltransferase (PEMT) is the unique endogenous regulatory enzyme that catalyzed PE methylation to PC. However, its expression, effects, mechanical and biological regulation in cardiomyocyte hypertrophy has not yet been elucidated. Our previous studies found that the expression of PEMT was increased, accompanied by mitochondria damage in the induction of cardiomyocyte hypertrophy by mechanical stimuli. While silence of PEMT could reverse the mitochondria damage and alleviate the hypertrophic process, suggesting that PEMT plays an important role in cardiomyocyte hypertrophy by affecting the structure and function of mitochondria. Based on the above, we hypothesized that PEMT was involved in cardiomyocyte hypertrophy by regulating mitochondria dynamics. To this end, the project intends to focus on the changes of PEMT expression, its action characteristics and underlying mechanism in myocardial hypertrophy caused by TAC-induced pressure overload and cardiomyocyte hypertrophy induced by mechanical and other hypertrophic stimuli. Aiming to provide a new direction for the exploration of mechanisms and prevention strategies for cardiovascular diseases such as cardiac hypertrophy and heart failure.

磷脂代谢紊乱参与了压力超负荷导致的心肌细胞肥大过程，但其作用机理尚未阐明。心肌细胞肥大中磷脂代谢紊乱的主要特征是磷脂酰乙醇胺（PE）含量降低、而磷脂酰胆碱（PC）合成增加。磷脂酰乙醇胺N-甲基转移酶（PEMT）是甲基化PE成为PC的唯一内源性调节酶，但其在力学负荷所致心肌细胞肥大中的变化、作用及力学生物学机制尚未见报道。我们前期结果显示：力学等肥厚性刺激诱导心肌细胞肥大时PEMT表达增加，并伴有线粒体损伤，沉默PEMT表达则可改善线粒体损伤并缓解心肌细胞肥大，提示PEMT可能通过影响线粒体的结构和功能介导心肌细胞肥大。因此，我们提出“PEMT通过调控线粒体动力学参与心肌细胞肥大”的假设。为此，本项目拟在主动脉缩窄所致心肌肥厚及力学等肥厚性刺激所致心肌细胞肥大模型中，研究PEMT的表达变化、作用特点、机制途径和潜在意义，为探索心肌肥厚及心力衰竭等心血管疾病的发生机制和防治策略提供新的方向。

心肌肥厚及其最终所致的心力衰竭是心血管疾病死亡的主要原因之一， 探讨其发病机制对临床治疗策略开发具有重要意义。多种迹象表明，甲基化PE成为PC的唯一内源性调节酶磷脂酰乙醇胺N-甲基转移酶（PEMT）可能与心肌细胞肥大进程相关，但其在心肌肥厚中表达变化、作用特点及力学生物学机制尚未见报道。本项目主要发现：1）PEMT 在压力超负荷诱导的肥厚心肌组织中、力学牵张刺激/AngII/PE 诱导的肥大心肌细胞中表达增加；2）体内外水平下调PEMT水平均可缓解心肌细胞肥大/心肌肥厚/心肌成纤维细胞活化/心肌纤维化程度；3）PEMT通过调控线粒体动力学失衡而参与心肌肥厚发展进程； 4）PEMT通过非复合物形式上调Drp1水平、下调Mfn2水平导致线粒体动力学失衡而诱导心肌肥厚进程；5）PEMT通过调节棕榈油酸-GSK3β通路参与心肌肥厚进程，此为PEMT作用新途径。本项目率先探讨了PEMT在心肌细胞肥大进程中的表达变化、作用特点，打破了“哺乳动物唯一内源性PC 合成催化酶 PEMT 的作用及机制研究目前大多集中在肝脏脂质代谢方面”的局面，保证了本项目的研究切入点具有理论创新性；并且，项目通过系统的研究明确了PEMT的表达增加促进了心肌细胞肥大进程，而降低其表达则可缓解心肌细胞肥大表型，为心肌肥厚的防治提供了新的靶点；最后，项目发现的PEMT调控线粒体动力学的机制及“PEMT-棕榈油酸-GSK3β通路-心肌肥厚”的新途径，均为完善 PEMT 的生物学功能提供理论依据，尤其棕榈油酸的心肌保护作用结果的发现，为心肌肥厚、心肌梗死等心血管疾病的治疗提供了新思路。