MiR-144 protects the heart from hyperglycemia-induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis
MiR-144 protects the heart from hyperglycemia-induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis
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MiR™144 通过调节线粒体生物发生和心肌细胞凋亡来保护心脏免受高血糖引起的损伤
DOI：
10.1096/fj.201901838r
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发表时间：
2020-02-01
期刊：
影响因子：
4.8
通讯作者：
Hua, Fei
中科院分区：
文献类型：
--
作者：
Tao, Lichan;Huang, Xiaoli;Hua, Fei
尽管microRNA（miRNAs，miRs）在高血糖性心功能不全中的作用尚不清楚，但已有证据显示其作为糖尿病心肌病生物标志物的潜力。在这项研究中，高糖（HG）诱导线粒体生物发生显著受损，表现为线粒体结构失调、线粒体DNA含量降低和生物发生相关mRNA水平降低，并伴有细胞凋亡增加。miR-144在HG诱导的心肌细胞和链脲佐菌素（STZ）激发的心脏样品中被鉴定为减少。强制miR-144表达增强线粒体生物合成并抑制细胞凋亡，而miR-144抑制则表现出相反的结果。Rac-1被鉴定为miR-144的靶基因。Rac-1水平降低激活AMPK磷酸化和PGC-1α脱乙酰化，导致线粒体生物合成增加和细胞凋亡减少。重要的是，miR-144的全身中和减轻了STZ治疗后的线粒体疾病和心室功能障碍。此外，血浆miR-144在伴有心功能不全的糖尿病患者中显著降低。受试者-操作者特征曲线显示，血浆miR-144可以特异性预测糖尿病患者发生心功能不全。总之，这项研究提供了强有力的证据，表明miR-144通过靶向Rac-1改善线粒体生物合成和减少细胞凋亡来保护心脏免受高血糖诱导的损伤。因此，强制miR-144表达可能是治疗高血糖诱导的心功能不全的保护性策略。
Several lines of evidence have revealed the potential of microRNAs (miRNAs, miRs) as biomarkers for detecting diabetic cardiomyopathy, although their functions in hyperglycemic cardiac dysfunction are still lacking. In this study, mitochondrial biogenesis was markedly impaired induced by high glucose (HG), as evidenced by dysregulated mitochondrial structure, reduced mitochondrial DNA contents, and biogenesis‐related mRNA levels, accompanied by increased cell apoptosis. MiR‐144 was identified to be decreased in HG‐induced cardiomyocytes and in streptozotocin (STZ)‐challenged heart samples. Forced miR‐144 expression enhanced mitochondrial biogenesis and suppressed cell apoptosis, while miR‐144 inhibition exhibited the opposite results. Rac‐1 was identified as a target gene of miR‐144. Decreased Rac‐1 levels activated AMPK phosphorylation and PGC‐1α deacetylation, leading to increased mitochondrial biogenesis and reduced cell apoptosis. Importantly, the systemic neutralization of miR‐144 attenuated mitochondrial disorder and ventricular dysfunction following STZ treatment. Additionally, plasma miR‐144 decreased markedly in diabetic patients with cardiac dysfunction. The receiver‐operator characteristic curve showed that plasma miR‐144 could specifically predict diabetic patients developing cardiac dysfunction. In conclusion, this study provides strong evidence suggesting that miR‐144 protects heart from hyperglycemia‐induced injury by improving mitochondrial biogenesis and decreasing cell apoptosis via targeting Rac‐1. Forced miR‐144 expression might, thus, be a protective strategy for treating hyperglycemia‐induced cardiac dysfunction.