PDF(Pubmed)
Abstract：
Pathological cardiac hypertrophy is an important cause of heart failure(HF). Recent studies reveal that glucagon-like peptide-1 receptor (GLP1R) agonists can improve mortality and left ventricular ejection fraction in the patients with type 2 diabetes and HF. The present study aims to investigate whether semaglutide, a long-acting GLP1R agonist, can ameliorate cardiac hypertrophy induced by pressure overload, and explore the potential mechanism. The rats were performed transverse aortic constriction (TAC) to mimic pressure overload model. The rats were divided into four groups including Sham, TAC, TAC + semaglutide, and TAC + semaglutide + HCQ (hydroxychloroquine, an inhibitor of mitophagy). The rats in each experimental group received their respective interventions for 4 weeks. The parameters of left ventricular hypertrophy(LVH) were measured by echocardiography, Hematoxylin-eosin (HE) staining, western-blot and immunohistochemistry (IHC), respectively. The changes of mitophagy were reflected by detecting cytochrome c oxidase subunit II (COXII), LC3II/LC3I, mitochondria, and autophagosomes. Meanwhile, NLRP3, Caspase-1, and interleukin-18 were detected to evaluate the activation of NLRP3 inflammasome in each group. The results suggest that LVH, impaired mitophagy, and activation of NLRP3 inflammasome were present in TAC rats. Semaglutide significantly reduced LVH, improve mitophagy, and down-regulated NLRP3 inflammatory signal pathway in TAC rats. However, the reversed effect of semaglutide on cardiac hypertrophy was abolished by HCQ, which restored the activation of NLRP3 inflammasome suppressed by improved mitophagy. In conclusion, semaglutide ameliorates the cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome. Semaglutide may be a novel potential option for intervention of cardiac hypertrophy induced by pressure overload.
摘要：
病理性心肌肥厚是心衰(HF)的重要缘由。最近的研究表明，胰高血糖素样肽-1受体（GLP1R）激动剂可以改善2型糖尿病和HF患者的死亡率和左心室射血分数。本研究旨在调查司马鲁肽，长效GLP1R激动剂，可以改善压力超负荷引起的心肌肥厚，并探索潜在的机制。大鼠行横主动脉缩窄(TAC)模拟压力超负荷模型。将大鼠分为四组，包括Sham，TAC,TAC+司马鲁肽,和TAC+司马鲁肽+HCQ(羟氯喹，线粒体自噬的抑制剂)。每个实验组的大鼠接受各自的干预4周。超声心动图检测左心室肥厚(LVH)参数,苏木精-伊红(HE)染色,蛋白质印迹和免疫组织化学（IHC），分别。通过检测细胞色素C氧化酶亚基II（COXII）反映了线粒体自噬的变化，LC3II/LC3I,线粒体,和自噬体。同时,检测NLRP3、Caspase-1和白细胞介素-18,评价各组NLRP3炎性体的活化情况。结果表明,LVH,线粒体自噬受损，TAC大鼠存在NLRP3炎性体的激活。塞马鲁肽显著降低LVH，改善线粒体自噬，下调TAC大鼠NLRP3炎症信号通路。然而,舒马鲁肽对心肌肥厚的逆转作用被HCQ废除，它恢复了由改善的线粒体自噬抑制的NLRP3炎性体的激活。总之,司马鲁肽通过改善心脏线粒体自噬抑制NLRP3炎性体的激活来改善心肌肥厚。塞马鲁肽可能是干预压力超负荷引起的心脏肥大的新的潜在选择。
