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  3. Reduced FNDC5-AMPK signaling in diabetic atrium increases the susceptibility of atrial fibrillation by impairing mitochondrial dynamics and activating NLRP3 inflammasome

Reduced FNDC5-AMPK signaling in diabetic atrium increases the susceptibility of atrial fibrillation by impairing mitochondrial dynamics and activating NLRP3 inflammasome

  • Biochem Pharmacol. 2024 Aug 10:229:116476. doi: 10.1016/j.bcp.2024.116476.
Shan Meng 1,  Xin Chen 1,  Jikai Zhao 2,  Xinyi Huang 2,  Yuting Huang 2,  Tao Huang 2,  Zijun Zhou 2,  Wenpu Ren 3,  Tao Hong 4,  Jinfeng Duan 5,  Liming Yu 6,  Huishan Wang 7
Affiliations

Affiliations

  • 1 Postgraduate Training Base of General Hospital of Northern Theater Command, Jinzhou Medical University, Jinzhou, Liaoning, 121001, PR China; State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China.
  • 2 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China.
  • 3 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China; Postgraduate College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, PR China.
  • 4 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China; Postgraduate College, Dalian Medical University, Dalian, Liaoning, 116000, PR China.
  • 5 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China; Postgraduate College, China Medical University, Shenyang, Liaoning, 110122, PR China.
  • 6 State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China. Electronic address: lmyu2012@163.com.
  • 7 Postgraduate Training Base of General Hospital of Northern Theater Command, Jinzhou Medical University, Jinzhou, Liaoning, 121001, PR China; State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China. Electronic address: huishanw@126.com.
PMID: 39128588 DOI: 10.1016/j.bcp.2024.116476
Abstract

Fibronectin type III domain-containing protein 5 (FNDC5) exerts potential anti-arrhythmic effects. However, the function and mechanism of FNDC5 in diabetes-associated atrial fibrillation (AF) remain unknown. In this study, bioinformatics analysis, in vivo and in vitro experiments were conducted to explore the alteration and role of FNDC5 in diabetes-related atrial remodeling and AF susceptibility. RNA Sequencing data from atrial samples of permanent AF patients and diabetic mice exhibited significantly decreased FNDC5 at the transcriptional level, which was in line with the protein expression in diabetic mice as well as high glucose and palmitic acid (HG+PA) injured atrial myocytes. Diabetic mice exhibited adverse atrial remodeling and increased AF inducibility. Moreover, reduced atrial FNDC5 was accompanied with exacerbated NOD-like Receptor pyrin domain containing 3 (NLRP3) activation and disturbed mitochondrial fission and fusion processes, as evidenced by decreased expressions of optic atrophy 1 (OPA-1), mitofusin (MFN-1, MFN-2) and increased phosphorylation of dynamin-related protein 1 (Ser616). These effects were validated in HG+PA-treated atrial myocytes. Critically, FNDC5 overexpression remarkably enhanced cellular antioxidant capacity by upregulating the expressions of superoxide dismutase (SOD1, SOD2) level. In addition, HG+PA-induced mitochondrial dysfunction was ameliorated by FNDC5 overexpression as evidenced by improved mitochondrial dynamics and membrane potential. Moreover, NLRP3 inflammasome-mediated inflammation was reduced by FNDC5 overexpression, and AMPK signaling might serve as the key down-stream effector. The present study demonstrated that reduced atrial FNDC5-AMPK signaling contributed to the pathogenesis of diabetes- associated AF by impairing mitochondrial dynamics and activating the NLRP3 inflammasome. These findings provide promising therapeutic avenues for diabetes-associated AF.

Keywords

Atrial fibrillation; Diabetes; FNDC5; Mitochondrial dynamics; NLRP3 inflammasome.

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