College of Physical Education, Taiyuan University of Technology, Taiyuan Shanxi, 030024, China.
Division of Sports Science and Physical Education, Tsinghua University, Beijing, 100084, China.
Mol Cell Biochem. 2024 Dec;479(12):3459-3470. doi: 10.1007/s11010-024-04950-0. Epub 2024 Feb 22.
Obesity has been identified as an independent risk factor for cardiovascular disease. Recent reports have highlighted the significance of stimulator of interferon genes (STING)-NOD-like receptor protein 3 (NLRP3) signaling pathway mediated pyroptosis, and inflammation in cardiovascular disease. Previous studies have demonstrated that exercise training effectively prevents cardiac pyroptosis and inflammation in high-fat diet (HFD)-fed mice. However, it is currently unknown whether exercise reduces pyroptosis and inflammation in obese hearts by targeting the STING-NLRP3 signaling pathway. We investigated the impact of an 8-week aerobic exercise regimen on cardiac function, pyroptosis, inflammation, and the STING-NLRP3 signaling pathway in HFD-induced obese mice. Additionally, to explore the underlying mechanism of STING in exercise-mediated cardioprotection, we administered intraperitoneal injections of the STING agonist diABZI to the mice. Furthermore, to investigate the role of the STING-NLRP3 signaling pathway in HFD-induced cardiac dysfunction, we administered adeno-associated virus 9 (AAV9) encoding shRNA targeting STING (shRNA-STING) via tail vein injection to knockdown STING expression specifically in mouse hearts. After one week of AAV9 injection, we intraperitoneally injected nigericin as an NLRP3 agonist. We first found that aerobic exercise effectively suppressed HFD-mediated upregulation of STING and NLRP3 in the hearts. Moreover, we demonstrated that the protective effect of aerobic exercise in HFD-induced cardiac dysfunction, pyroptosis, and inflammation was impaired by stimulating the STING pathway using diABZI. Additionally, activation of the NLRP3 with nigericin abolished the ameliorative effect of STING deficiency in HFD-induced cardiac dysfunction, pyroptosis, and inflammation. Based on these findings, we concluded that 8-week aerobic exercise alleviates HFD-induced cardiac dysfunction, pyroptosis, and inflammation by targeting STING-NLRP3 signaling pathway. Inhibition of STING-NLRP3 signaling pathway may serve as a promising therapeutic strategy against obesity-induced cardiomyopathy.
肥胖已被确定为心血管疾病的独立危险因素。最近的报告强调了干扰素基因刺激物 (STING)-NOD 样受体蛋白 3 (NLRP3) 信号通路介导的细胞焦亡和炎症在心血管疾病中的重要性。先前的研究表明，运动训练可有效预防高脂肪饮食 (HFD) 喂养小鼠的心脏细胞焦亡和炎症。然而，目前尚不清楚运动是否通过靶向 STING-NLRP3 信号通路来减少肥胖心脏中的细胞焦亡和炎症。我们研究了 8 周有氧运动对 HFD 诱导肥胖小鼠心脏功能、细胞焦亡、炎症和 STING-NLRP3 信号通路的影响。此外，为了探索 STING 在运动介导的心脏保护中的潜在机制，我们向小鼠腹腔内注射 STING 激动剂 diABZI。此外，为了研究 STING-NLRP3 信号通路在 HFD 诱导的心脏功能障碍中的作用，我们通过尾静脉注射编码针对 STING 的短发夹 RNA (shRNA-STING) 的腺相关病毒 9 (AAV9)，特异性敲低小鼠心脏中的 STING 表达。AAV9 注射 1 周后，我们腹腔内注射 Nigericin 作为 NLRP3 激动剂。我们首先发现有氧运动有效抑制了 HFD 介导的心脏中 STING 和 NLRP3 的上调。此外，我们证明，使用 diABZI 刺激 STING 通路会损害有氧运动在 HFD 诱导的心脏功能障碍、细胞焦亡和炎症中的保护作用。此外，Nigericin 激活 NLRP3 会消除 STING 缺乏在 HFD 诱导的心脏功能障碍、细胞焦亡和炎症中的改善作用。基于这些发现，我们得出结论，8 周有氧运动通过靶向 STING-NLRP3 信号通路缓解 HFD 诱导的心脏功能障碍、细胞焦亡和炎症。抑制 STING-NLRP3 信号通路可能成为治疗肥胖诱导性心肌病的有前途的治疗策略。
