on December 29, 2005
Published online before print December 29, 2005, doi: 10.1161/01.ATV.0000201932.32678.7e
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Submitted on October 5, 2005
Accepted on December 14, 2005
TNF-
Contributes to Endothelial Dysfunction in Ischemia/Reperfusion Injury
Cuihua Zhang *;
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.
* To whom correspondence should be addressed. 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.
Key words: coronary artery disease • endothelial function • nitric oxide • microcirculation • reactive oxygen species
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