期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 21, 期 1, 页码 58-71出版社
WILEY
DOI: 10.1111/jcmm.12938
关键词
myocardial ischaemia; vagal nerve stimulation; mitochondrial dynamics; mitochondrial function; AMP-activated protein kinase; subtype-3 of muscarinic acetylcholine receptor; cardioprotection
资金
- National Natural Science Foundation of China [81120108002, 81473203, 81302774]
- Specialized Research Fund for the Doctoral Program of Higher Education [20130201130008]
Mitochondrial dynamicsfission and fusionare 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 (CaMKK) 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/CaMKK/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/CaMKK/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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