{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T22:23:55Z","timestamp":1779920635706,"version":"3.53.1"},"reference-count":33,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2012,11,5]],"date-time":"2012-11-05T00:00:00Z","timestamp":1352073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Reactive oxygen species (ROS) production is an important mechanism in myocardial ischemia and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of major sources of ROS in the heart. Previous studies showed that vagus nerve stimulation (VNS) is beneficial in treating ischemic heart diseases. However, the effect of VNS on ROS production remains elusive. In this study, we investigated the role of VNS onischemia-induced ROS production. Our results demonstrated that VNS alleviated the myocardial injury, attenuated the cardiac dysfunction, reserved the antioxidant enzyme activity and inhibited the formation of ROS as evidenced by the decreased NADPH oxidase (Nox) activity and superoxide fluorescence intensity as well as the expression of p67phox, Rac1 and nitrotyrosine. Furthermore, VNS resulted in the phosphorylation and activation of adenosine monophosphate activated protein kinase (AMPK), which in turn led to an inactivation of Nox by protein kinase C (PKC); however, the phenomena were repressed by the administration of a muscarinic antagonist atropine. Taken together, these data indicate that VNS decreases ROS via AMPK-PKC-Nox pathway; this may have potential importance for the treatment of ischemic heart diseases.<\/jats:p>","DOI":"10.3390\/ijms131114311","type":"journal-article","created":{"date-parts":[[2012,11,5]],"date-time":"2012-11-05T11:09:37Z","timestamp":1352113777000},"page":"14311-14325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Protection against Ischemia-Induced Oxidative Stress Conferred by Vagal Stimulation in the Rat Heart: Involvement of the AMPK-PKC Pathway"],"prefix":"10.3390","volume":"13","author":[{"given":"Shan-Shan","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Jiang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Jin","family":"Zang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2012,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s00380-010-0029-9","article-title":"Oxidative stress versus antioxidant defenses in patients with acute myocardial infarction","volume":"26","author":"Bagatini","year":"2011","journal-title":"Heart Vessels"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1006\/jmcc.1997.0497","article-title":"Significant levels of oxidants are generated by isolated cardiomyocytes during ischemia prior to reperfusion","volume":"29","author":"Vanden","year":"1997","journal-title":"J. Mol. Cell. Cardiol"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/jcb.23371","article-title":"Isorhamnetin inhibits H2O2-induced activation of the intrinsic apoptotic pathway in H9c2 cardiomyocytes through scavenging reactive oxygen species and ERK inactivation","volume":"113","author":"Sun","year":"2012","journal-title":"J. Cell. Biochem"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.coph.2005.10.008","article-title":"NADPH oxidase and heart failure","volume":"6","author":"Murdoch","year":"2006","journal-title":"Curr. Opin. Pharmacol"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1152\/physrev.00044.2005","article-title":"The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology","volume":"87","author":"Bedard","year":"2007","journal-title":"Physiol. Rev"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.yjmcc.2009.04.004","article-title":"NADPH oxidase signaling and cardiac myocyte function","volume":"47","author":"Akki","year":"2009","journal-title":"J. Mol. Cell. Cardiol"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/s10495-006-6304-7","article-title":"Ischemia induces nuclear NOX2 expression in cardiomyocytes and subsequently activates apoptosis","volume":"11","author":"Meischl","year":"2006","journal-title":"Apoptosis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1136\/jcp.56.3.194","article-title":"Increased Nox2 expression in human cardiomyocytes after acute myocardial infarction","volume":"56","author":"Krijnen","year":"2003","journal-title":"J. Clin. Pathol"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1016\/S0735-1097(03)00471-6","article-title":"Increased myocardial NADPH oxidase activity in human heart failure","volume":"41","author":"Heymes","year":"2003","journal-title":"J. Am. Coll. Cardiol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1161\/01.RES.0000099504.30207.F5","article-title":"Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy","volume":"93","author":"Byrne","year":"2003","journal-title":"Circ. Res"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1007\/s00392-004-0137-6","article-title":"On the genesis of myocardial ischemia","volume":"93","author":"Sroka","year":"2004","journal-title":"Z. Kardiol"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1113\/jphysiol.2004.082198","article-title":"Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model","volume":"565","author":"Jardine","year":"2005","journal-title":"J. Physiol"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.cardiores.2006.01.013","article-title":"Autonomic imbalance and immune activation in chronic heart failure\u2014Pathophysiological links","volume":"70","author":"Jankowska","year":"2006","journal-title":"Cardiovasc. Res"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.1440-1681.2011.05505.x","article-title":"Tumour necrosis factor-alpha and its receptors in the beneficial effects of vagal stimulation after myocardial infarction in rats","volume":"38","author":"Kong","year":"2011","journal-title":"Clin. Exp. Pharmacol. Physiol"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1161\/01.CIR.0000105721.71640.DA","article-title":"Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats","volume":"109","author":"Li","year":"2004","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.ejheart.2008.07.016","article-title":"Long term vagal stimulation in patients with advanced heart failure: First experience in man","volume":"10","author":"Schwartz","year":"2008","journal-title":"Eur. J. Heart Fail"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1161\/CIRCULATIONAHA.104.525493","article-title":"Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein","volume":"112","author":"Ando","year":"2005","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1113\/jphysiol.2007.138461","article-title":"Nitric oxide mediates the vagal protective effect on ventricular fibrillation via effects on action potential duration restitution in the rabbit heart","volume":"583","author":"Brack","year":"2007","journal-title":"J. Physiol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.freeradbiomed.2006.04.015","article-title":"Insulin generates free radicals in human fibroblasts ex vivo by a protein kinase C-dependent mechanism, which is inhibited by pravastatin","volume":"41","author":"Ceolotto","year":"2006","journal-title":"Free Radic. Biol. Med"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S227","DOI":"10.1002\/mnfr.201100147","article-title":"Coenzyme Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK\/PKC\/NADPH oxidase signaling pathway","volume":"55","author":"Tsai","year":"2011","journal-title":"Mol. Nutr. Food Res"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1161\/01.RES.85.2.147","article-title":"Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro","volume":"85","author":"Siwik","year":"1999","journal-title":"Circ. Res"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"C840","DOI":"10.1152\/ajpcell.1998.275.3.C840","article-title":"Tissue distribution of immunoreactive mouse extracellular superoxide dismutase","volume":"275","author":"Ookawara","year":"1998","journal-title":"Am. J. Physiol"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/j.1463-1326.2011.01369.x","article-title":"Inhibition of NADPH oxidase alleviates experimental diabetes-induced myocardial contractile dysfunction","volume":"13","author":"Roe","year":"2011","journal-title":"Diabetes Obes. Metab"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.bbrc.2006.08.052","article-title":"Resistin worsens cardiac ischaemia-reperfusion injury","volume":"349","author":"Rothwell","year":"2006","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/j.1432-1033.1997.00259.x","article-title":"The AMP-activated protein kinase\u2014Fuel gauge of the mammalian cell?","volume":"246","author":"Hardie","year":"1997","journal-title":"Eur. J. Biochem"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5730","DOI":"10.4049\/jimmunol.173.9.5730","article-title":"Protein kinase C delta is required for p47phox phosphorylation and translocation in activated human monocytes","volume":"173","author":"Bey","year":"2004","journal-title":"J. Immunol"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1161\/ATVBAHA.107.155762","article-title":"Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism","volume":"27","author":"Ceolotto","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol"},{"key":"ref_28","unstructured":"(1996). Guide for the Care and Use of Laboratory Animals, National Academies Press. National Institutes of Health publication No. 85\u201323."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1161\/CIRCRESAHA.108.188243","article-title":"IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR","volume":"104","author":"Krishnamurthy","year":"2009","journal-title":"Circ. Res"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.cardfail.2007.04.009","article-title":"Tissue kallikrein and kinin infusion rescues failing myocardium after myocardial infarction","volume":"13","author":"Yao","year":"2007","journal-title":"J. Card Fail"},{"key":"ref_31","first-page":"H562","article-title":"Accumulation of cAMP augments dynamic vagal control of heart rate","volume":"275","author":"Nakahara","year":"1998","journal-title":"Am. J. Physiol"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.lfs.2005.05.087","article-title":"Vagal stimulation suppresses ischemia-induced myocardial interstitial norepinephrine release","volume":"78","author":"Kawada","year":"2006","journal-title":"Life Sci"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1016\/j.freeradbiomed.2011.01.031","article-title":"Differential effects of NADPH oxidase and xanthine oxidase inhibition on sympathetic reinnervation in postinfarct rat hearts","volume":"50","author":"Lee","year":"2011","journal-title":"Free Radic. Biol. Med"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/13\/11\/14311\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:53:19Z","timestamp":1760219599000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/13\/11\/14311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,11,5]]},"references-count":33,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2012,11]]}},"alternative-id":["ijms131114311"],"URL":"https:\/\/doi.org\/10.3390\/ijms131114311","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,11,5]]}}}