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.
Highlights
Catestatin (CST) is a 21 amino acid-residue, hydrophobic neuroendocrine peptide derived from chromogranin A (ChgA)[1]
CST (25 nM, 50 nM and 100 nM) pretreatment decreased lactate dehydrogenase (LDH) leakage and cardiac troponin I level in perfusate at different reperfusion time point, which indicated that CST pretreatment lowered the ischemia reperfusion (I/R) injury, especially CST at 100 nM exhibited well protection
We identify the CST is an endogenous ligand of the M2 receptor
Summary
Catestatin (CST) is a 21 amino acid-residue, hydrophobic neuroendocrine peptide derived from chromogranin A (ChgA)[1]. Many clinical trials have revealed an association between plasma CST level and cardiac diseases including acute myocardial infarction, heart failure and cardiac remodeling[12,13,14,15]. Gi/o protein is an important intracellular target of M2 and M4 receptors[21] Based on these previous findings, it is reasonably to speculate that M receptor may play essential roles in CST’s protective effects during cardiac I/R injury. We presented novel evidence that CST directly bound to and activated M2 receptor to attenuate ER-stress linked apoptosis via activation of ERK1/2 and Akt pathways in cardiac I/R
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