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Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways

Authors :
Xiaoli Yang
Rongchuan Yue
Jun Zhang
Xiaoqun Zhang
Yukai Liu
Caiyu Chen
Xinquan Wang
Hao Luo
Wei Eric Wang
Xiongwen Chen
Huixia Judy Wang
Pedro A. Jose
Hongyong Wang
Chunyu Zeng
Source :
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 7, Iss 14 (2018)
Publication Year :
2018
Publisher :
Wiley, 2018.

Abstract

Background Ischemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI. Methods and Results Adult male Sprague‐Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff‐perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal‐regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin‐mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin‐mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes. Conclusions These results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.

Details

Language :
English
ISSN :
20479980
Volume :
7
Issue :
14
Database :
Directory of Open Access Journals
Journal :
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.569a30cf8b430cb56615398bc80a15
Document Type :
article
Full Text :
https://doi.org/10.1161/JAHA.116.005171