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

Authors: Xue, Run-Qing  Sun, Lei  Yu, Xiao-Jiang  Li, Dong-Ling  Zang, Wei-Jin 
Citation: Xue RQ, etal., J Cell Mol Med. 2017 Jan;21(1):58-71. doi: 10.1111/jcmm.12938. Epub 2016 Aug 5.
Pubmed: (View Article at PubMed) PMID:27491814
DOI: Full-text: DOI:10.1111/jcmm.12938

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 Ca(2+) /calmodulin-dependent protein kinase kinase ß (CaMKKß) during myocardial ischaemia. Treatment with subtype-3 of muscarinic acetylcholine receptor (M3 R) antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide or AMPK inhibitor Compound C abolished the protective effects of VNS on mitochondrial dynamics and function, suggesting that M3 R/CaMKKß/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 M3 R/CaMKKß/AMPK pathway, to attenuate ISO-induced cardiac damage in rats. Targeting mitochondrial dynamics may provide a novel therapeutic strategy in IHD.

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RGD Object Information
RGD ID: 12910831
Created: 2017-06-26
Species: All species
Last Modified: 2017-06-26
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.