Semaglutide protects against diabetes‐associated cardiac inflammation via Sirt3‐dependent RKIP pathway

作者：Kaibin Lin, Wang Ai, Changlin Zhai, Yun Zhao, Huilin Hu, Dong Huang, Qiwei Zhai, Yan Yan, Junbo Ge · 发表于：British Journal of Pharmacology · 年份：2024 · DOI：10.1111/bph.17327 · 被引用次数：31 · 研究领域：Apelin-related biomedical research、Diabetes Treatment and Management、Cardiovascular Function and Risk Factors

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiovascular benefits in diabetic patients, but the underlying mechanisms remain incompletely understood. Semaglutide, a novel long-acting GLP-1RA, has shown a reduced risk of cardiovascular events. Based on these results, we investigated the therapeutic potential of semaglutide in diabetic cardiomyopathy and sought to elucidate the underlying mechanisms. EXPERIMENTAL APPROACH: Mice with diabetes induced by high-fat diet/streptozotocin were treated with semaglutide. The mechanisms underlying the cardioprotective effects of semaglutide were analysed using animal and cell experiments. KEY RESULTS: In diabetic mice, semaglutide alleviated metabolic disorders, ameliorated myocardial fibrosis, improved cardiac function, antagonized oxidative stress and suppressed cardiomyocyte apoptosis. More significantly, semaglutide attenuated cardiac inflammation through restoring Raf kinase inhibitor protein (RKIP) expression and inhibiting downstream TANK-binding kinase 1 (TBK1)-NF-κB pathway. Meanwhile, decreased RKIP expression and activated TBK1-NF-κB signalling pathway were also found in tissues from human diabetic hearts. RKIP deficiency exacerbated cardiac inflammation and offset the cardioprotective effect of semaglutide in diabetic mice. Moreover, semaglutide also restored the expression level of Sirtuin 3(Sirt3), which served as a modulator against cardiac inflammation by regulating RKIP-dependent p...