Lin Kaibin, Wang Ai, Zhai Changlin, Zhao Yun, Hu Huilin, Huang Dong, Zhai Qiwei, Yan Yan, Ge Junbo
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Cardiovascular Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing, China.
Br J Pharmacol. 2025 Apr;182(7):1561-1581. doi: 10.1111/bph.17327. Epub 2024 Dec 22.
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.
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.
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 pathway. In diabetic mice, RKIP deficiency abolished the cardioprotective benefits conferred by the Sirt3 activator honokiol. We also found that cAMP/PKA signalling, rather than glucose lowering, contributed to the anti-inflammatory effect of semaglutide through Sirt3-dependent RKIP pathway.
Semaglutide exerted cardioprotective effects against diabetic heart failure by alleviating cardiac inflammation through Sirt3-dependent RKIP signalling pathway.
胰高血糖素样肽-1受体激动剂（GLP-1RAs）对糖尿病患者具有心血管益处，但其潜在机制仍未完全明确。司美格鲁肽是一种新型长效GLP-1RA，已显示出降低心血管事件风险的作用。基于这些结果，我们研究了司美格鲁肽在糖尿病性心肌病中的治疗潜力，并试图阐明其潜在机制。
用高脂饮食/链脲佐菌素诱导糖尿病小鼠，并用司美格鲁肽进行治疗。使用动物和细胞实验分析司美格鲁肽心脏保护作用的潜在机制。
在糖尿病小鼠中，司美格鲁肽减轻了代谢紊乱，改善了心肌纤维化，改善了心脏功能，拮抗了氧化应激并抑制了心肌细胞凋亡。更显著的是，司美格鲁肽通过恢复Raf激酶抑制蛋白（RKIP）的表达并抑制下游的TANK结合激酶1（TBK1）-核因子κB（NF-κB）信号通路，减轻了心脏炎症。同时，在人类糖尿病心脏组织中也发现RKIP表达降低和TBK1-NF-κB信号通路激活。RKIP缺乏加剧了心脏炎症，并抵消了司美格鲁肽对糖尿病小鼠的心脏保护作用。此外，司美格鲁肽还恢复了沉默调节蛋白3（Sirt3）的表达水平，Sirt3通过调节RKIP依赖途径作为心脏炎症的调节剂。在糖尿病小鼠中，RKIP缺乏消除了Sirt3激活剂厚朴酚赋予的心脏保护益处。我们还发现，环磷酸腺苷/蛋白激酶A（cAMP/PKA）信号通路而非降糖作用，通过Sirt3依赖的RKIP途径促成了司美格鲁肽的抗炎作用。
司美格鲁肽通过Sirt3依赖的RKIP信号通路减轻心脏炎症，对糖尿病心力衰竭发挥心脏保护作用。
