Vagal nerve stimulation improves mitochondrial dynamics via an M₃ receptor/CaMKKβ/AMPK pathway in isoproterenol-induced myocardial ischaemia

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• 作者：Run-Qing Xue ; Lei Sun ; Xiao-Jiang Yu ; Dong-Ling Li and Wei-Jin Zang
• 刊名：Journal of Cellular and Molecular Medicine
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：21
• 期：1
• 页码：58-71
• 全文大小：1461K
• ISSN：1582-4934

文摘

Mitochondrial dynamics—fission and fusion—are associated with ischaemic heart disease (IHD). This study explored the protective effect of vagal nerve stimulation (VNS) against isoproterenol (ISO)-induced myocardial ischaemia in a rat model and tested whether VNS plays a role in preventing disorders of mitochondrial dynamics and function. Isoproterenol not only caused cardiac injury but also increased the expression of mitochondrial fission proteins [dynamin-related peptide1 (Drp1) and mitochondrial fission protein1 (Fis-1)) and decreased the expression of fusion proteins (optic atrophy-1 (OPA1) and mitofusins1/2 (Mfn1/2)], thereby disrupting mitochondrial dynamics and leading to increase in mitochondrial fragments. Interestingly, VNS restored mitochondrial dynamics through regulation of Drp1, Fis-1, OPA1 and Mfn1/2; enhanced ATP content and mitochondrial membrane potential; reduced mitochondrial permeability transition pore (MPTP) opening; and improved mitochondrial ultrastructure and size. Furthermore, VNS reduced the size of the myocardial infarction and ameliorated cardiomyocyte apoptosis and cardiac dysfunction induced by ISO. Moreover, VNS activated AMP-activated protein kinase (AMPK), which was accompanied by phosphorylation of Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ) during myocardial ischaemia. Treatment with subtype-3 of muscarinic acetylcholine receptor (M₃R) antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide or AMPK inhibitor Compound C abolished the protective effects of VNS on mitochondrial dynamics and function, suggesting that M₃R/CaMKKβ/AMPK signalling are involved in mediating beneficial effects of VNS. This study demonstrates that VNS modulates mitochondrial dynamics and improves mitochondrial function, possibly through the M₃R/CaMKKβ/AMPK pathway, to attenuate ISO-induced cardiac damage in rats. Targeting mitochondrial dynamics may provide a novel therapeutic strategy in IHD.