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Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion.

Liao F, Zheng Y, Cai J, Fan J, Wang J, Yang J, Cui Q, Xu G, Tang C, Geng B - Sci Rep (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed mechanism of CST’s protective effects in cardiac I/R injury.CST acts as an endogenous M2 receptor agonist, activates M2 receptor and causes inhibition of adenylyl cyclase (AC) activity via the α subunit (αi) of Gi, thereby decreasing cAMP level while stimulating by isoproterenol or forskolin. During cardiac I/R, CST binds to M2 receptor and activates ERK1/2 and PI3 K/Akt signaling pathway to reduce ER-stress response and cell apoptosis.
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f8: Proposed mechanism of CST’s protective effects in cardiac I/R injury.CST acts as an endogenous M2 receptor agonist, activates M2 receptor and causes inhibition of adenylyl cyclase (AC) activity via the α subunit (αi) of Gi, thereby decreasing cAMP level while stimulating by isoproterenol or forskolin. During cardiac I/R, CST binds to M2 receptor and activates ERK1/2 and PI3 K/Akt signaling pathway to reduce ER-stress response and cell apoptosis.

Mentions: In the present study, we identify the CST is an endogenous ligand of the M2 receptor. CST pretreatment activates M2 receptor, thereby activates PI3 K and ERK1/2 pathway results in reducing ER stress-induced cell apoptosis and increasing cell survival (Fig. 8), thus lowers infarct size and recovers cardiac pump function under I/R.


Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion.

Liao F, Zheng Y, Cai J, Fan J, Wang J, Yang J, Cui Q, Xu G, Tang C, Geng B - Sci Rep (2015)

Proposed mechanism of CST’s protective effects in cardiac I/R injury.CST acts as an endogenous M2 receptor agonist, activates M2 receptor and causes inhibition of adenylyl cyclase (AC) activity via the α subunit (αi) of Gi, thereby decreasing cAMP level while stimulating by isoproterenol or forskolin. During cardiac I/R, CST binds to M2 receptor and activates ERK1/2 and PI3 K/Akt signaling pathway to reduce ER-stress response and cell apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4645123&req=5

f8: Proposed mechanism of CST’s protective effects in cardiac I/R injury.CST acts as an endogenous M2 receptor agonist, activates M2 receptor and causes inhibition of adenylyl cyclase (AC) activity via the α subunit (αi) of Gi, thereby decreasing cAMP level while stimulating by isoproterenol or forskolin. During cardiac I/R, CST binds to M2 receptor and activates ERK1/2 and PI3 K/Akt signaling pathway to reduce ER-stress response and cell apoptosis.
Mentions: In the present study, we identify the CST is an endogenous ligand of the M2 receptor. CST pretreatment activates M2 receptor, thereby activates PI3 K and ERK1/2 pathway results in reducing ER stress-induced cell apoptosis and increasing cell survival (Fig. 8), thus lowers infarct size and recovers cardiac pump function under I/R.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, P.R. China.

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.

No MeSH data available.


Related in: MedlinePlus