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.
Highlights
In ischaemic heart disease (IHD), which continues to be the main cause of the death worldwide, heart mitochondria directly sustain injury [1]
Otherwise, compared with the sham group, ISO reduced hemodynamic parameters, mean arterial pressure (MAP), LV developed pressure (LVDP) and ÆdP/dtmax, whereas the effect was vagal nerve stimulation (VNS) decreases cardiomyocyte apoptosis induced by ISO
Compared with the ISO-treated with VNS (ISO+VNS) group, both AMPK and M3R inhibition increased p-dynamin-related peptide1 (Drp1) and fission protein1 (Fis-1) expression, whereas expression of optic atrophy-1 (OPA1) and mitofusins1 and 2 (Mfn1/2) were significantly reduced (P < 0.05; Fig. 8A–F), indicating AMPK may function as an essential link between VNS treatment and mitochondrial dynamics and M3R acts as a bridge for VNS to activate the calmodulin-dependent protein kinase kinase b (CaMKKb)/AMPK pathway
Summary
In ischaemic heart disease (IHD), which continues to be the main cause of the death worldwide, heart mitochondria directly sustain injury [1]. Dynamic mitochondria constantly undergo fusion and fission, with these two opposing processes regulated by mitochondrial fusion [optic atrophy-1 (OPA1), and mitofusins and 2 (Mfn1/2)] and fission proteins [dynamin-related peptide (Drp1), and mitochondrial fission protein (Fis-1)] respectively [8]. Both mitochondrial fission and fusion are essential for cell metabolic function and facilitate segregation of dysfunctional or damaged mitochondria before apoptosis [9, 10]. Regulation of proteins mediating mitochondrial dynamics or inhibition of excessive mitochondrial fission attenuates mitochondrial dysfunction to improve MI [11, 12] Targeting these proteins that regulate mitochondrial dynamics could prevent cardiac injury occurring due to myocardial ischaemia
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