Open AccessGastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways
Author(s) -
Yang Xiaoli,
Yue Rongchuan,
Zhang Jun,
Zhang Xiaoqun,
Liu Yukai,
Chen Caiyu,
Wang Xinquan,
Luo Hao,
Wang Wei Eric,
Chen Xiongwen,
Wang Huixia Judy,
Jose Pedro A.,
Wang Hongyong,
Zeng Chunyu
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.116.005171
Subject(s) - medicine , gastrin , reperfusion injury , endocrinology , ischemia , protein kinase b , cardioprotection , cardiac function curve , cardiology , signal transduction , heart failure , biology , microbiology and biotechnology , secretion
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 ERK 1/2 (extracellular signal‐regulated kinase 1/2), AKT (protein kinase B), and STAT 3 (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 ERK 1/2, AKT , or STAT 3 abrogated the gastrin‐mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK 2R blocker CI 988 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.