Adaptive changes in the heart by exercise have been shown to reduce the risk of cardiovascular disease, and M2 Acetylcholine receptor (M2AChR), a receptor abundantly present on cardiac parasympathetic nerves, is closely associated with the development of cardiovascular disease. The present study intends to investigate whether exercise can regulate endoplasmic reticulum stress (ERS) and mitophagy through M2AChR to resist myocardial ischemia-reperfusion (I/R) injury and to elucidate its mechanism of action.
Results:
Exercise enhanced parasympathetic nerve function and increased myocardial M2AChR protein expression in I/R rats. In addition, it promoted the protein expression of MFN2 and inhibited the expression of Drp1, Chop, PINK1/Parkin, and PERK/eIF2α/ATF4 signaling pathways, effectively reducing mitophagy, ERS, and apoptosis. At the cellular level, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) reduced hypoxia/reoxygenation (H/R)-induced ERS through the downregulated expression of PERK/eIF2α/ATF4 pathway proteins in H9C2 cardiomyocytes. When intervened with M2AChR inhibitors, the levels of ERS and phosphorylation levels of the PERK/eIF2α/ATF4 pathway were increased in H/R cells.
Innovation and Conclusion:
Exercise intervention activated the parasympathetic state in rats. It inhibited myocardial mitophagy and ERS levels, and reduced myocardial apoptosis through M2AChR, thereby resisting I/R-induced myocardial injury and improving cardiac function. Antioxid. Redox Signal. 40, 209–221.
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References
1.
BadrovMB, WoodKN, LalandeS, et al.Effects of 6 months of exercise-based cardiac rehabilitation on autonomic function and neuro-cardiovascular stress reactivity in coronary artery disease patients. J Am Heart Assoc, 2019; 8(17):e012257; doi: 10.1161/JAHA.119.012257
2.
BandoniRL, Bricher ChoquePN, DellêH, et al.Cholinergic stimulation with pyridostigmine modulates a heart-spleen axis after acute myocardial infarction in spontaneous hypertensive rats. Sci Rep, 2021; 11(1):9563; doi: 10.1038/s41598-021-89104-8
3.
BedfordTG, TiptonCM, et al.Maximum oxygen consumption of rats and its changes with various experimental procedures. J Appl Physiol Respir Environ Exerc Physiol, 1979; 47(6):1278–1283; doi: 10.1152/jappl.1979.47.6.1278
4.
BoziLH, JannigPR, RolimN, et al.Aerobic exercise training rescues cardiac protein quality control and blunts endoplasmic reticulum stress in heart failure rats. J Cell Mol Med, 2016; 20(11):2208–2212; doi: 10.1111/jcmm.12894
5.
CheangWS, WongWT, ZhaoL, et al.PPARδ is required for exercise to attenuate endoplasmic reticulum stress and endothelial dysfunction in diabetic mice. Diabetes, 2017; 66(2):519–528; doi: 10.2337/db15-1657
6.
ChengjiW, XianjinF. Exercise protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway in rats. J Cell Physiol, 2019; 234(2):1682–1688; doi: 10.1002/jcp.27038
7.
ChenM, ZhouX, YuL, et al.Low-level vagus nerve stimulation attenuates myocardial ischemic reperfusion injury by antioxidative stress and antiapoptosis reactions in canines. J Cardiovasc Electrophysiol, 2016; 27(2):224–231; doi: 10.1111/jce.12850
8.
Figueroa-ValverdeL, Diaz-CedilloF, Garcia-CerveraE, et al.Effect of progesterone-carbachol derivative on perfusion pressure and coronary resistance in isolated rat heart: Via activation of the M2 muscarinic receptor. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2014; 158(1):73–79; doi: 10.5507/bp.2012.010
9.
Fiuza-LucesC, Santos-LozanoA, JoynerM, et al.Exercise benefits in cardiovascular disease: Beyond attenuation of traditional risk factors. Nat Rev Cardiol, 2018; 15(12):731–743; doi: 10.1038/s41569-018-0065-1
10.
GhahremaniR, DamirchiA, SalehiI, et al.Mitochondrial dynamics as an underlying mechanism involved in aerobic exercise training-induced cardioprotection against ischemia-reperfusion injury. Life Sci, 2018; 213:102–108; doi: 10.1016/j.lfs.2018.10.035
11.
Gumpper-FedusK, ParkKH, MaH, et al.MG53 preserves mitochondrial integrity of cardiomyocytes during ischemia reperfusion-induced oxidative stress. Redox Biol, 2022; 54:102357; doi: 10.1016/j.redox.2022.102357
12.
HangP, ZhaoJ, SuZ, et al.Choline inhibits ischemia-reperfusion-induced cardiomyocyte autophagy in rat myocardium by activating Akt/mTOR signaling. Cell Physiol Biochem, 2018; 45(5):2136–2144; doi: 10.1159/000488049
13.
HuH, TianM, DingC, et al.The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol, 2019; 9:3083; doi: 10.3389/fimmu.2018.03083
14.
HughesD, MallucciGR. The unfolded protein response in neurodegenerative disorders—Therapeutic modulation of the PERK pathway. FEBS J, 2019; 286(2):342–355; doi: 10.1111/febs.14422
15.
IntachaiK, ChattipakornSC, ChattipakornN, et al.Revisiting the cardioprotective effects of acetylcholine receptor activation against myocardial ischemia/reperfusion injury. Int J Mol Sci, 2018; 19(9):2466; doi: 10.3390/ijms19092466
16.
LiYZ, WuH, LiuD, et al.cFLIPL alleviates myocardial ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress. Cardiovasc Drugs Ther, 2021; doi: 10.1007/s10557-021-07280-1
17.
LiaoF, ZhengY, CaiJ, et al.Author correction: Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion. Sci Rep, 2020; 10(1):19543; doi: 10.1038/s41598-020-76697-9
18.
LiuL, ZhaoM, YuX, et al.Pharmacological modulation of vagal nerve activity in cardiovascular diseases. Neurosci Bull, 2019; 35(1):156–166; doi: 10.1007/s12264-018-0286-7
19.
NeriM, RiezzoI, PascaleN, et al.Ischemia/reperfusion injury following acute myocardial infarction: A critical issue for clinicians and forensic pathologists. Mediators Inflamm, 2017; 2017:7018393; doi: 10.1155/2017/7018393
20.
NuntaphumW, PongkanW, WongjaikamS, et al.Vagus nerve stimulation exerts cardioprotection against myocardial ischemia/reperfusion injury predominantly through its efferent vagal fibers. Basic Res Cardiol, 2018; 113(4):22; doi: 10.1007/s00395-018-0683-0
21.
PasqualinRC, MostardaCT, SouzaLE, et al.Sevoflurane preconditioning during myocardial ischemia-reperfusion reduces infarct size and preserves autonomic control of circulation in rats. Acta Cir Bras, 2016; 31(5):338–345; doi: 10.1590/S0102-865020160050000008
22.
SilvaLEV, GeraldiniVR, de OliveiraBP, et al.Comparison between spectral analysis and symbolic dynamics for heart rate variability analysis in the rat. Sci Rep, 2017; 7(1):8428; doi: 10.1038/s41598-017-08888-w
23.
SongZC, ChenL, ZhangD, et al.[Rosuvastatin protects acute myocardial infarction rats through autophagy regulation via AMPK signaling]. Zhonghua Yi Xue Za Zhi, 2018; 98(43):3536–3541. Chinese; doi: 10.3760/cma.j.issn.0376-2491.2018.43.015
24.
SunL, ZhaoM, YuXJ, et al.Cardioprotection by acetylcholine: A novel mechanism via mitochondrial biogenesis and function involving the PGC-1α pathway. J Cell Physiol, 2013; 228(6):1238–1248; doi: 10.1002/jcp.24277
25.
SunL, ZhaoM, YangY, et al.Acetylcholine attenuates hypoxia/reoxygenation injury by inducing mitophagy through PINK1/parkin signal pathway in H9c2 cells. J Cell Physiol, 2016; 231(5):1171–1181; doi: 10.1002/jcp.25215
26.
TaoL, BeiY, LinS, et al.Exercise training protects against acute myocardial infarction via improving myocardial energy metabolism and mitochondrial biogenesis. Cell Physiol Biochem, 2015; 37(1):162–175; doi: 10.1159/000430342
27.
WangM, WangRY, ZhouJH, et al.Calenduloside E ameliorates myocardial ischemia-reperfusion injury through regulation of AMPK and mitochondrial OPA1. Oxid Med Cell Longev, 2020; 2020:2415269; doi: 10.1155/2020/2415269
28.
WangS, HanHM, PanZW, et al.Choline inhibits angiotensin II-induced cardiac hypertrophy by intracellular calcium signal and p38 MAPK pathway. Naunyn Schmiedebergs Arch Pharmacol, 2012; 385(8):823–831; doi: 10.1007/s00210-012-0740-4
29.
WangYH, HuH, WangSP, et al.Exercise benefits cardiovascular health in hyperlipidemia rats correlating with changes of the cardiac vagus nerve. Eur J Appl Physiol, 2010; 108(3):459–468; doi: 10.1007/s00421-009-1232-1
30.
YangY, ZhaoL, MaJ. Penehyclidine hydrochloride preconditioning provides cardiac protection in a rat model of myocardial ischemia/reperfusion injury via the mechanism of mitochondrial dynamics mechanism. Eur J Pharmacol, 2017; 813:130–139; doi: 10.1016/j.ejphar.2017.07.031
31.
YaoL, ChenH, WuQ, et al.Hydrogen-rich saline alleviates inflammation and apoptosis in myocardial I/R injury via PINK-mediated autophagy. Int J Mol Med, 2019; 44(3):1048–1062; doi: 10.3892/ijmm.2019.4264
32.
YiC, SongM, SunL, et al.Asiatic acid alleviates myocardial ischemia-reperfusion injury by inhibiting the ROS-mediated mitochondria-dependent apoptosis pathway. Oxid Med Cell Longev, 2022; 2022:3267450; doi: 10.1155/2022/3267450
33.
YuL, LiB, ZhangM, et al.Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury: role of RISK and SAFE pathways interaction. Apoptosis, 2016; 21(7):809–824; doi: 10.1007/s10495-016-1246-1
34.
ZhangCX, ChengY, LiuDZ, et al.Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats. J Nanobiotechnol, 2019; 17(1):18; doi: 10.1186/s12951-019-0451-9
35.
ZhaoD, SunY, TanY, et al.Short-duration swimming exercise after myocardial infarction attenuates cardiac dysfunction and regulates mitochondrial quality control in aged mice. Oxid Med Cell Longev, 2018; 2018:4079041; doi: 10.1155/2018/4079041
36.
ZhuW, LiuF, WangL, et al.pPolyHb protects myocardial H9C2 cells against ischemia-reperfusion injury by regulating the Pink1-Parkin-mediated mitochondrial autophagy pathway. Artif Cells Nanomed Biotechnol, 2019; 47(1):1248–1255; doi: 10.1080/21691401.2019.1594243
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