Cytokine‐induced coronary endothelial cell barrier dysfunction

Abstract

Heart disease is one of the leading causes of death in the United States, killing nearly one million people every year. Inflammatory mediators or cytokines are released following myocardial infarction (MI) and ischemia/reperfusion (I/R) injury. These cytokines, of which IL-1β, IL-6, and TNFα are among the most important, propagate the activation of a multitude of signaling pathways that lead to deleterious changes in the structure and function of the coronary microvascular endothelium. Because these pathways are complex and interactive, therapeutic targeting of cytokine-induced early molecular events has proven relatively ineffective in combating detrimental effects of MI. Our objective is to determine the effects of MI on in vivo cytokine release and coronary permeability using a rat model as well as cytokine-induced changes in signaling mechanisms, junctional protein modifications and permeability using a coronary microvascular endothelial cell monolayer. IR injury of the left ventricle, induced by clamping and subsequent release of the left coronary artery, resulted in protein extravasation from the circulation to heart tissue as well as protein phosphorylation of the adherens junction component β-catenin. Administration of the above mentioned cytokines to cell monolayers resulted in significant increases in protein kinase C activation, myosin light chain phosphorylation, and albumin flux across the monolayer. These results identify endpoint molecular and structural alterations to the coronary microvasculature, elicited by IR injury and cytokine release, which represent potential therapeutic targets. This work supported by Scott and White Memorial Hospital Dept. of Surgery.