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

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.

Langendorff; RISK (reperfusion injury salvage kinase); SAFE (survivor activating factor enhancement); gastrin; ischemia/reperfusion injury; reperfusion injury salvage kinase.