Journal
JOURNAL OF SURGICAL RESEARCH
Volume 152, Issue 1, Pages 76-83Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jss.2008.02.022
Keywords
phosphorylation; serine kinases; adherens junction; beta-catenin; cytokine; ischemia/reperfusion; protein kinase C; endothelium; myosin light chain kinase
Categories
Funding
- Scott and White Memorial Hospital
- Departments of Surgery and Research/Education
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Background. 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 and ischemia/reperfusion injury. These cytokines, of which interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (TNF-alpha) are among the most important, propagate the activation of a multitude of signaling pathways, such as the protein kinase C (PKC) and myosin light chain kinase (MLCK) pathways, which lead to deleterious changes in the structure and function of the coronary microvascular endothelium. Methods. The effects of cytokines on rat heart microvascular endothelial cell monolayer integrity, PKC activity, and adherens junction protein alteration were examined. Further, an in vivo rat coronary ischemia/ reperfusion injury model was used to determine vascular leakage and TNF-a release. Results. Administration of the above mentioned cytokines to cell monolayers resulted in significant increases in PKC activation, gap formation, and hyper-permeability across the monolayer and beta-catenin phosphorylation/reorganization. Inhibition of conventional PKC and MLCK attenuated permeability increases. Ischemia/reperfusion injury to the left ventricle resulted in TNF-a release as well as conventional PKC- and MLCK-dependent protein extravasation from the circulation to the heart tissue. Conclusion. These results identify the conventional PKC and MILCK pathways as important factors in coronary endothelial dysfunction elicited by IR injury and cytokine release. Further examination of these molecular signaling cascades has the potential of identifying targets for therapeutic intervention following ischemic events in the heart. (c) 2009 Elsevier Inc. All rights reserved.
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