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A more recent version of this article appeared on March 1, 2008

Published online before print February 14, 2008
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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070834

Accepted for publication November 20, 2007.

Article

Endothelial Cysteinyl Leukotriene 2 Receptor Expression Mediates Myocardial Ischemia-Reperfusion Injury

Wei Jiang*, Sean R. Hall*, Michael P.W. Moos*, Richard Yang Cao*, Satoshi Ishii{dagger}, Kofo O. Ogunyankin{ddagger}, Luis G. Melo*{ddagger}, and Colin D. Funk*{sect}@

From the Departments of Physiology,* Medicine,{ddagger} and Biochemistry,{sect} Queen's University, Kingston, Canada; and the Department of Biochemistry and Molecular Biology,{dagger} University of Tokyo, Tokyo, Japan

@ To whom correspondence should be addressed. E-mail: funkc{at}queensu.ca.


  Abstract

Cysteinyl leukotrienes (CysLTs) have been implicated as inflammatory mediators of cardiovascular disease. Three distinct CysLT receptor subtypes transduce the actions of CysLTs but the role of the endothelial CysLT2 receptor (CysLT2R) in cardiac function is unknown. Here, we investigated the role of CysLT2R in myocardial ischemia-reperfusion (I/R) injury using transgenic (tg) mice overexpressing human CysLT2R in vascular endothelium and nontransgenic (ntg) littermates. Infarction size in tg mice increased 114% compared with ntg mice 48 hours after I/R; this increase was blocked by the CysLT receptor antagonist BAY-u9773. Injection of 125I-albumin into the systemic circulation revealed significantly enhanced extravasation of the label in tg mice, indicating increased leakage of the coronary endothelium, combined with increased incidence of hemorrhage and cardiomyocyte apoptosis. Expression of proinflammatory genes such as Egr-1, VCAM-1, and ICAM was significantly increased in tg mice relative to ntg controls. Echocardiographic assessment 2 weeks after I/R revealed decreased anterior wall thickness in tg mice. Furthermore, the postreperfusion time constant {tau} of isovolumic relaxation was significantly increased in tg animals, indicating diastolic dysfunction. These results reveal that endothelium-targeted overexpression of CysLT2R aggravates myocardial I/R injury by increasing endothelial permeability and exacerbating inflammatory gene expression, leading to accelerated left ventricular remodeling, induction of peri-infarct zone cellular apoptosis, and impaired cardiac performance.






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Copyright © 2008 by the American Society for Investigative Pathology.