Published online before print December 29, 2005, doi: 10.1161/01.ATV.0000201932.32678.7e
© 2006 American Heart Association, Inc.
Vascular Biology |
TNF-
Contributes to Endothelial Dysfunction in Ischemia/Reperfusion Injury
From the Departments of Anethesiology, Surgery, and Physiology (C.Z., X.X.), LSU Health Sciences Center, New Orleans, La; the Department of Medical Physiology (W.W., L.K.), College of Medicine, Texas A&M University System Health Science Center, College Station, Tex; the Section of Cardiovascular Sciences (L.M.), Baylor College of Medicine, the Methodist Hospital, and the DeBakey Heart Center, Houston, Tex; and the Department of Physiology (B.J.P., G.J.B., W.M.C.), LSU Health Sciences Center, New Orleans, La.
Correspondence to Cuihua Zhang, Departments of Anesthesiology, Surgery, and Physiology, School of Medicine, LSU Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112. E-mail czhang{at}lsuhsc.edu
Background— Despite the importance of endothelial function for coronary regulation, there is little information and virtually no consensus about the causal mechanisms of endothelial dysfunction in myocardial ischemia/reperfusion (I/R) injury. Because tumor necrosis factor-
(TNF-) is reportedly expressed during ischemia and can induce vascular inflammation leading to endothelial dysfunction, we hypothesized that this inflammatory cytokine may play a pivotal role in I/R injury-induced coronary endothelial dysfunction.
Methods and Results— To test this hypothesis, we used a murine model of I/R (30 minutes/90 minutes) in conjunction with neutralizing antibodies to block the actions of TNF-. TNF- expression was increased >4-fold after I/R. To determine whether TNF- abrogates endothelial function after I/R, we assessed endothelial-dependent (ACh) and endothelial-independent (SNP) vasodilation. In sham controls, ACh induced dose-dependent vasodilation that was blocked by the nitric oxide synthase (NOS) inhibitor L-NMMA (10 µmol/L), suggesting a key role for NO. In the I/R group, dilation to ACh was blunted, but SNP-induced dilation was preserved. Subsequent incubation of vessels with the superoxide (O2·–) scavenger (TEMPOL), or with the inhibitors of xanthine oxidase (allopurinol, oxypurinol), or previous administration of anti-TNF- restored endothelium-dependent dilation in the I/R group and reduced I/R-stimulated O2·– production in arteriolar endothelial cells. Activation of xanthine oxidase with I/R was prevented by allopurinol or anti–TNF-.
Conclusions— These results suggest that myocardial I/R initiates expression of TNF-, which induces activation of xanthine oxidase and production of O2·–, leading to coronary endothelial dysfunction.
We examined the role of TNF- in endothelial dysfunction after myocardial ischemia-reperfusion (I/R) injury. I/R injury compromised endothelium-dependent dilation to acetylcholine (ACh). TNF- expression was increased >4-fold after I/R. Anti-TNF- restored vasodilation to ACh and reduced xanthine oxidase activity, the production of O2·–.
Key Words: coronary artery disease • endothelial function • nitric oxide • microcirculation • reactive oxygen species
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