title: Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion.
abstract: Catestatin (CST) is a catecholamine secretion inhibiting peptide as non-competitive inhibitor of nicotinic acetylcholine receptor. CST play a protective role in cardiac ischemia/reperfusion (I/R) but the molecular mechanism remains unclear. Cardiomyocytes endogenously produced CST and its expression was reduced after I/R. CST pretreatment decreased apoptosis especially endoplasmic reticulum (ER) stress response during I/R. The protection of CST was confirmed in H9c2 cardiomyoblasts under Anoxia/reoxygenation (A/R). In contrast, siRNA-mediated knockdown of CST exaggerated ER stress induced apoptosis. The protective effects of CST were blocked by extracellular signal-regulated kinases 1/2 (ERK1/2) inhibitor PD90895 and phosphoinositide 3-kinase (PI3 K) inhibitor wortmannin. CST also increased ERK1/2 and protein kinase B (Akt) phosphorylation and which was blocked by atropine and selective type 2 muscarinic acetylcholine (M2) receptor, but not type 1 muscarinic acetylcholine (M1) receptor antagonist. Receptor binding assay revealed that CST competitively bound to the M2 receptor with a 50% inhibitory concentration of 25.7 nM. Accordingly, CST inhibited cellular cAMP stimulated by isoproterenol or forskolin, and which was blocked by selective M2 receptor antagonist. Our findings revealed that CST binds to M2 receptor, then activates ERK1/2 and PI3 K/Akt pathway to inhibit ER stress-induced cell apoptosis resulting in attenuation cardiac I/R injury.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liao
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.|Center for Noncoding RNA Medicine, Peking University Health Science Center Beijing 100191, China.
authors.forename: Jichun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.|Center for Noncoding RNA Medicine, Peking University Health Science Center Beijing 100191, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.
authors.forename: Guoheng
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.
authors.forename: Chaoshu
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.|Center for Noncoding RNA Medicine, Peking University Health Science Center Beijing 100191, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Geng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D053379:Chromogranin A / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D020935:MAP Kinase Signaling System; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009206:Myocardium / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D053379:Chromogranin A; D018721:Muscarinic Agonists; D010446:Peptide Fragments; D043585:Receptor, Muscarinic M2; C109084:chromogranin A (344-364); D019869:Phosphatidylinositol 3-Kinases