TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury.
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-alpha (TNF-alpha) 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.


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-alpha. TNF-alpha expression was increased >4-fold after I/R. To determine whether TNF-alpha 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 micromol/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-alpha 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-alpha.


CONCLUSIONS
These results suggest that myocardial I/R initiates expression of TNF-alpha, which induces activation of xanthine oxidase and production of O2*-, leading to coronary endothelial dysfunction.
Zhang
Cuihua
C
Department of Anesthesiology, LSU Health Sciences Center, New Orleans, LA 70112, USA. czhang@lsuhsc.edu
Xu
Xiangbin
X
Potter
Barry J
BJ
Wang
Wei
W
Kuo
Lih
L
Michael
Lloyd
L
Bagby
Gregory J
GJ
Chilian
William M
WM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001160:Arterioles / Q000276:immunology / Q000378:metabolism; D003331:Coronary Vessels / Q000276:immunology / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology; D004730:Endothelium, Vascular / Q000276:immunology* / Q000503:physiopathology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000503:physiopathology*; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism
D000906:Antibodies; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D000109:Acetylcholine