Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou City, 213003, China.
Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou City, 213003, China.
Mol Cell Endocrinol. 2019 Feb 5;481:95-103. doi: 10.1016/j.mce.2018.11.015. Epub 2018 Nov 29.
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.
Mice were subjected to repetitive 5% O for 30 s and 21% O for 30 s, for a total of 8 h/day for 4 weeks. Subsequently, mice received subcutaneous injection of saline or rhGLP-1 (100 μg/kg, three times per day). Cardiac function, myocardial apoptosis and fibrosis, energy metabolism, and mitochondrial biogenesis were examined for evaluation of cardiac injury.
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) α and PPARγ. 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-1α and Akt signaling.
rhGLP-1 protects against IH-induced cardiac injury by improving myocardial energy metabolism and enhancing the early adaptive changes of mitochondrial biogenesis.
阻塞性睡眠呼吸暂停综合征是一种与间歇性低氧（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，已被用作治疗急性心肌梗死、扩张型心肌病和晚期心力衰竭的有前途的治疗剂。然而，GLP-1 是否能保护心脏免受 IH 引起的损伤尚不清楚。因此，在本研究中，我们评估了重组人 GLP-1（rhGLP-1）对小鼠心脏健康的影响。
小鼠接受重复 5% O 30s 和 21% O 30s，总时间为 8h/d，持续 4 周。随后，小鼠接受皮下注射生理盐水或 rhGLP-1（100μg/kg，每日 3 次）。评估心脏功能、心肌细胞凋亡和纤维化、能量代谢和线粒体生物发生，以评估心脏损伤。
rhGLP-1 显著逆转了 IH 暴露小鼠舒张功能（E/A 比值）的降低。IH 诱导明显的心肌细胞凋亡和心肌纤维化。此外，IH 导致心肌从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 PPARγ 下调。此外，IH 导致线粒体 DNA（mtDNA）复制和转录减少，mtDNA 含量降低，线粒体超微结构受损。rhGLP-1 通过激活 PGC-1α 和 Akt 信号转导消除了这些变化。
rhGLP-1 通过改善心肌能量代谢和增强线粒体生物发生的早期适应性变化来保护心脏免受 IH 引起的损伤。
