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Published online 26 February 2001. doi:10.1083/jcb.152.5.857
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© The Rockefeller University Press, 0021-9525/2001/3/857/ $5.00
The Journal of Cell Biology, Volume 152, Number 5, March 5, 2001 857-866

Original Article

{alpha}4-Integrin Mediates Neutrophil-induced Free Radical Injury to Cardiac Myocytes

Betty Y. Poona, Christopher A. Wardd, Conan B. Cooperb, Wayne R. Gilesc, Alan R. Burnse, and Paul Kubesa,c
a Immunology Research Group, University of Calgary, Calgary, Alberta T2N 1N4, Canada
b Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta T2N 1N4, Canada
c Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 1N4, Canada
d Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada
e Department of Medicine, Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, Texas 77030

Correspondence to: Paul Kubes, Immunology Research Group, Health Sciences Center, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada. Tel:(403) 220-8558 Fax:(403) 283-1267 E-mail:pkubes{at}ucalgary.ca.

Previous work has demonstrated that circulating neutrophils (polymorphonuclear leukocytes [PMNs]) adhere to cardiac myocytes via ß2-integrins and cause cellular injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme system. Since PMNs induced to leave the vasculature (emigrated PMNs) express the {alpha}4-integrin, we asked whether (a) these PMNs also induce myocyte injury via NADPH oxidase; (b) ß2-integrins (CD18) still signal oxidant production, or if this process is now coupled to the {alpha}4-integrin; and (c) dysfunction is superoxide dependent within the myocyte or at the myocyte–PMN interface. Emigrated PMNs exposed to cardiac myocytes quickly induced significant changes in myocyte function. Myocyte shortening was decreased by 30–50% and rates of contraction and relaxation were reduced by 30% within the first 10 min. Both {alpha}4-integrin antibody (Ab)-treated PMNs and NADPH oxidase–deficient PMNs were unable to reduce myocyte shortening. An increased level of oxidative stress was detected in myocytes within 5 min of PMN adhesion. Addition of an anti–{alpha}4-integrin Ab, but not an anti-CD18 Ab, prevented oxidant production, suggesting that in emigrated PMNs the NADPH oxidase system is uncoupled from CD18 and can be activated via the {alpha}4-integrin. Addition of exogenous superoxide dismutase (SOD) inhibited all parameters of dysfunction measured, whereas overexpression of intracellular SOD within the myocytes did not inhibit the oxidative stress or the myocyte dysfunction caused by the emigrated PMNs. These findings demonstrate that profound molecular changes occur within PMNs as they emigrate, such that CD18 and associated intracellular signaling pathways leading to oxidant production are uncoupled and newly expressed {alpha}4-integrin functions as the ligand that signals oxidant production. The results also provide pathological relevance as the emigrated PMNs have the capacity to injure cardiac myocytes through the {alpha}4-integrin–coupled NADPH oxidase pathway that can be inhibited by extracellular, but not intracellular SOD.

Key Words: heart, neutrophils, integrins, free radicals, oxidant


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