HMGA1在心肌重构代谢紊乱中的作用和机制研究

Cardiac remodeling is a common pathological process in the development of various cardiovascular diseases into heart failure. The metabolic disorder of cardiac myocytes plays a key role in the occurrence and development of cardiac remodeling. HMGA1 is a newly discovered non-structural histone chromosomal protein, which regulates various transcription factors’ function. HMGA1 plays an important role in tumorigenesis, invasion, metabolism, embryonic development regulation, cell proliferation, differentiation, apoptosis, aging. In our preliminary study, HMGA1 expression was up-regulated in a mouse model of cardiac remodeling. The expression of HMGA1 was up-regulated in angiotensin II stimulated cardiomyocytes. Overexpression of HMGA1 attenuates myocardial remodeling response to angiotensin II stimulation, suggesting that HMGA1 plays an important role in cardiac remodeling. Thus, our study intends to further clarify the role of HMGA1 in cardiac remodeling and metabolic disorders by using HMGA1 cardiomypcyte -specific transgenic mice and in vitro experiments models. Our study may explore new strategies for the prevention and treatment of cardiac remodeling and heart failure.

心肌重构是临床上多种心血管疾病发展为心力衰竭所共有的病理过程。心肌细胞量代谢紊乱，对心肌重构的发生发展起到关键调节作用。高迁移率族A1 (HMGA1)是一类新发现的非结构性组蛋白的染色体蛋白，调控多种转录因子的作用。HMGA1在肿瘤的发生和侵袭、代谢、胚胎发育调控、细胞增殖、分化与凋亡，衰老等各种生命活动中发挥重要作用。本项目前期预实验结果显示在心肌重构的小鼠模型上， HMGA1表达上调。血管紧张素II刺激心肌细胞后，HMGA1表达上调。HMGA1心脏过表达减轻血管紧张素II刺激导致的小鼠心肌重构，这表明HMGA1参与心肌重构的发生发展。因此，本项目拟应用HMGA1心肌细胞特异性转基因小鼠及体外实验，进一步明确HMGA1在心肌重构和代谢紊乱中的作用，并探讨其潜在的调控机制，以期探索心肌重构和心力衰竭防治的新策略。

近年来，尽管心肌肥厚的发生机制已取得重要进展，但是临床上尚无十分有效的防治方法，心力衰竭的发病率和死亡率仍居高不下。本项目采用心脏特异性HMGA1转基因小鼠构建在体心肌肥厚模型，探讨HMGA1在心肌肥厚中的作用及机制。我们发现HMGA1在心肌肥厚小鼠心脏和心肌细胞中表达先升高后降低；HMGA1转基因小鼠减轻血管紧张素II诱导的心肌肥厚、纤维化和心功能恶化和心脏血流动力学的紊乱。通过机制研究我们发现HMGA1通过调控PPARα改善心肌能量代谢和线粒体氧化呼吸。总之，心肌重构过程中增加HMGA1会改善心肌PPARα-心肌能量代谢通路，改善线粒体功能。增加心脏中HMGA1的表达可能会在将来成为心力衰竭的有效疗法。