Recombinant human glucagon-like peptide-1 protects against chronic intermittent hypoxia by improving myocardial energy metabolism and mitochondrial biogenesis
Recombinant human glucagon-like peptide-1 protects against chronic intermittent hypoxia by improving myocardial energy metabolism and mitochondrial biogenesis
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DOI：
10.1016/j.mce.2018.11.015
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发表时间：
2019-02-05
影响因子：
4.1
通讯作者：
Hua, Fei
中科院分区：
文献类型：
--
作者：
Tao, Lichan;Wang, Long;Hua, Fei
背景和目的：阻塞性睡眠呼吸暂停综合征是一种与间歇性缺氧（IH）相关的慢性疾病，是心血管疾病的重要危险因素。胰高血糖素样肽（GLP-1）是一种天然存在的肠促胰岛素，在急性心肌梗死、扩张型心肌病和晚期心力衰竭的治疗中被用作有前途的治疗剂。然而，GLP-1是否可以保护IH诱导的心脏损伤仍不清楚。因此，在这项研究中，我们评估了重组人GLP-1（rhGLP-1）对小鼠心脏健康的影响。方法：小鼠反复接受5%O-2 30 s和21%O-2 30 s，共8 h/d，持续4周。随后，小鼠接受皮下注射生理盐水或rhGLP-1（100 μ g/kg，每天三次）。心脏功能，心肌细胞凋亡和纤维化，能量代谢和线粒体生物合成进行了检查，用于评估心脏injure.Results：舒张功能（E/A比）在小鼠暴露于IH的减少被显着逆转rhGLP-1。IH可诱导心肌细胞凋亡和心肌纤维化。此外，IH导致心肌中脂肪酸代谢向葡萄糖代谢转变，过氧化物酶体增殖物激活受体（PPAR）α和PPAR γ下调。此外，IH导致线粒体DNA（mtDNA）的复制和转录减少，连同减少的mtDNA含量和线粒体超微结构受损。结论：rhGLP-1通过改善心肌能量代谢，增强线粒体生物合成的早期适应性改变，对IH诱导的心肌损伤具有保护作用。
Background and aims: Obstructive sleep apnea syndrome is a chronic disease associated with intermittent hypoxia (IH) and is an important risk factor for cardiovascular disease. Glucagon-like peptide (GLP-1) is a naturally occurring incretin used as a promising therapeutic agent in the treatment of acute myocardial infarction, dilated cardiomyopathy, and advanced heart failure. However, whether GLP-1 can protect against IH-induced cardiac injury is still unclear. Accordingly, in this study, we evaluated the effects of recombinant human GLP-1 (rhGLP-1) on cardiac health in mice.Methods: Mice were subjected to repetitive 5% O-2 for 30 s and 21% O-2 for 30 s, for a total of 8 h/day for 4 weeks. Subsequently, mice received subcutaneous injection of saline or rhGLP-1 (100 mu g/kg, three times per day). Cardiac function, myocardial apoptosis and fibrosis, energy metabolism, and mitochondrial biogenesis were examined for evaluation of cardiac injury.Results: A reduction in diastolic function (E/A ratio) in mice exposed to IH was significantly reversed by rhGLP-1. IH induced marked cardiomyocyte apoptosis and myocardial fibrosis. Additionally, IH resulted in a shift from fatty acid to glucose metabolism in the myocardium with downregulation of peroxisome proliferator-activated receptor (PPAR) alpha and PPAR gamma. Moreover, IH caused a reduction in mitochondrial DNA (mtDNA) replication and transcription, together with reduced mtDNA content and impaired mitochondrial ultrastructure. These changes were abolished by rhGLP-1 via activation of PGC-1 alpha and Akt signaling.Conclusions: rhGLP-1 protects against IH-induced cardiac injury by improving myocardial energy metabolism and enhancing the early adaptive changes of mitochondrial biogenesis.