Division of Cardiology and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Cardiology, China-Japan Friendship Hospital, No. 2 Yinghua Dongjie, Beijing, 100029, China.
Cardiovasc Diabetol. 2019 Jan 11;18(1):7. doi: 10.1186/s12933-019-0811-7.
Metabolic abnormalities have been implicated as a causal event in diabetic cardiomyopathy (DCM). However, the mechanisms underlying cardiac metabolic disorder in DCM were not fully understood.
Db/db mice, palmitate treated H9c2 cells and primary neonatal rat cardiomyocytes were employed in the current study. Microarray data analysis revealed that PGC-1β may play an important role in DCM. Downregulation of PGC-1β relieved palmitate induced cardiac metabolism shift to fatty acids use and relevant lipotoxicity in vitro. Bioinformatics coupled with biochemical validation was used to confirm that PGC-1β was one of the direct targets of miR-30c. Remarkably, overexpression of miR-30c by rAAV system improved glucose utilization, reduced excessive reactive oxygen species production and myocardial lipid accumulation, and subsequently attenuated cardiomyocyte apoptosis and cardiac dysfunction in db/db mice. Similar effects were also observed in cultured cells. More importantly, miR-30c overexpression as well as PGC-1β knockdown reduced the transcriptional activity of PPARα, and the effects of miR-30c on PPARα was almost abated by PGC-1β knockdown.
Our data demonstrated a protective role of miR-30c in cardiac metabolism in diabetes via targeting PGC-1β, and suggested that modulation of PGC-1β by miR-30c may provide a therapeutic approach for DCM.
代谢异常被认为是糖尿病心肌病（DCM）的一个因果事件。然而，DCM 中心脏代谢紊乱的机制尚未完全阐明。
本研究采用 Db/db 小鼠、棕榈酸处理的 H9c2 细胞和原代新生大鼠心肌细胞。微阵列数据分析显示，PGC-1β 可能在 DCM 中发挥重要作用。PGC-1β 的下调缓解了棕榈酸诱导的体外心脏代谢向脂肪酸利用和相关脂毒性的转变。生物信息学结合生化验证用于确认 PGC-1β 是 miR-30c 的直接靶标之一。值得注意的是，rAAV 系统过表达 miR-30c 可改善葡萄糖利用，减少过量活性氧的产生和心肌脂质积累，从而减轻 db/db 小鼠的心肌细胞凋亡和心功能障碍。在培养的细胞中也观察到类似的效果。更重要的是，miR-30c 的过表达以及 PGC-1β 的敲低降低了 PPARα 的转录活性，并且 miR-30c 对 PPARα 的影响几乎被 PGC-1β 的敲低所消除。
我们的数据表明，miR-30c 通过靶向 PGC-1β 在糖尿病心脏代谢中发挥保护作用，并表明 miR-30c 对 PGC-1β 的调节可能为 DCM 提供一种治疗方法。
