Endothelin-1 Release during the Early Phase of Reperfusion Is a Mediator of Myocardial Reperfusion Injury

• Published in: Cardiology Vol. 125; no. 4; pp. 242 - 249
• Main Authors: Tamareille, Sophie, Terwelp, Matthew, Amirian, James, Felli, Patricia, Zhang, Xiu Q., Barry, William H., Smalling, Richard W.
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland 01.01.2013
• Subjects: Animals; Apoptosis - physiology; bcl-2-Associated X Protein - metabolism; Calcium - metabolism; Coronary Vessels; Endothelin A Receptor Antagonists; Endothelin-1 - metabolism; Hemodynamics - physiology; Ligation; Male; Myocardial Infarction - physiopathology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - physiopathology; Myocytes, Cardiac - metabolism; Original Research; Peptides, Cyclic - pharmacology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rabbits; Left ventricular unloading; Intracellular calcium; Reperfusion injury; Endothelin-1; Apoptosis
• ISSN: 0008-6312; 1421-9751
• DOI: 10.1159/000350655

Purpose: In acute myocardial infarction, left ventricular (LV) unloading reduces endothelin-1 (ET-1) release. We tested that endogenous ET-1 released during acute myocardial infarction might mediate ischemia/reperfusion (I/R) injury by stimulating increased intracellular calcium concentration, [Ca 2+ ] i , and apoptosis. Methods: Rabbits were subjected to 1 h of coronary artery occlusion followed by 3 h of reperfusion. Unloading was initiated 15 min prior to reperfusion and was maintained during reperfusion. The control group was subjected to reperfusion. Animals were treated with ET-1 receptor antagonist BQ123. In parallel, isolated rabbit cardiomyocytes subjected to simulated I/R with or without ET-1 or BQ123, intracellular Ca 2+ and cell death were assessed with flow cytometry. Results: LV unloading prior to reperfusion reduced myocardial ET-1 release at 2 h of reperfusion. Infarct size was reduced in unloaded and BQ123 groups versus controls. LV unloading and BQ123 treatment reduced the percentage of apoptotic cells associated with increases in Bcl-2 protein levels in ischemic regions. BQ123 reduced both ET-1-induced [Ca 2+ ] i increase and cell death for myocytes subjected to stimulated I/R. Conclusion: We propose that components of reperfusion injury involve ET-1 release which stimulates calcium overload and apoptosis. Intravenous ET-1 receptor blockade prior to reperfusion may be a protective adjunct to reperfusion therapy in acute myocardial infarction patients.