title: Vagal nerve stimulation improves mitochondrial dynamics via an M3receptor/CaMKKβ/AMPK pathway in isoproterenol-induced myocardial ischaemia.
abstract: 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.
authors: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors: Run-Qing
authors: RQ
authors: Xue
authors: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors: Lei
authors: L
authors: Sun
authors: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors: Xiao-Jiang
authors: XJ
authors: Yu
authors: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors: Dong-Ling
authors: DL
authors: Li
authors: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors: Wei-Jin
authors: WJ
authors: Zang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000139:chemically induced / Q000378:metabolism; D017202:Myocardial Ischemia / Q000139:chemically induced* / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D055536:Vagus Nerve Stimulation / Q000379:methods
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D043587:Receptor, Muscarinic M3; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D007545:Isoproterenol
keywords: AMP-activated protein kinase; cardioprotection; mitochondrial dynamics; mitochondrial function; myocardial ischaemia; subtype-3 of muscarinic acetylcholine receptor; vagal nerve stimulation