Abstract-Inflammation is a condition that underscores many cardiovascular pathologies including endothelial dysfunction, but no link is yet established between the vascular pathology of the metabolic syndrome with a particular inflammatory cytokine. We hypothesized that impairments in coronary endothelial function in the obese condition the prediabetic metabolic syndrome is caused by TNF-␣ overexpression. To test this, we measured endothelium-dependent (acetylcholine) and -independent vasodilation (sodium nitroprusside) of isolated, pressurized coronary small arteries from lean control and Zucker obese fatty (ZOF, a model of prediabetic metabolic syndrome) rats. In ZOF rats, dilation to ACh was blunted compared with lean rats, but sodium nitroprusside-induced dilation was comparable. Superoxide (O 2 · Ϫ ) generation was elevated in vessels from ZOF rats compared with lean rats, and administration of the O 2 · Ϫ scavenger TEMPOL, NAD(P)H oxidase inhibitor (apocynin), or anti-TNF-␣ restored endothelium-dependent dilation in the ZOF rats. Real-time PCR and Western blotting revealed that mRNA and protein of TNF-␣ were higher in ZOF rats than that in lean rats, whereas eNOS protein levels were reduced in the ZOF versus lean rats. Immunostaining showed that TNF-␣ in ZOF rat heart is localized in endothelial cells and vascular smooth muscle cells. Expression of NAD(P)H subunits p22 and p40-phox were elevated in ZOF compared with lean animals. Administration of TNF-␣ more than 3 days also induced expression of these NAD(P)H subunits and abrogated endothelium-dependent dilation. In conclusion, the results demonstrate the endothelial dysfunction occurring in the metabolic syndrome is the result of effects of the inflammatory cytokine TNF-␣ and subsequent production of
Background-We hypothesized that the inflammatory cytokine tumor necrosis factor-␣ (TNF) produces endothelial dysfunction in type 2 diabetes. Methods and Results-In m Leprdb control mice, sodium nitroprusside and acetylcholine induced dose-dependent vasodilation, and dilation to acetylcholine was blocked by the NO synthase inhibitor N G -monomethyl-L-arginine. In type 2 diabetic (Lepr db ) mice, acetylcholine-or flow-induced dilation was blunted compared with m Lepr db , but sodium nitroprusside produced comparable dilation. In Lepr db mice null for TNF (db TNFϪ /db TNFϪ ), dilation to acetylcholine or flow was greater than in diabetic Lepr db mice and comparable to that in controls. Plasma concentration of TNF was significantly increased in Lepr db versus m Lepr db mice. Real-time polymerase chain reaction and Western blotting showed that mRNA and protein expression of TNF and nuclear factor-B were higher in Lepr db mice than in controls. Administration of anti-TNF or soluble receptor of advanced glycation end products attenuated nuclear factor-B and TNF expression in the Lepr db mice. Immunostaining results show that TNF in mouse heart is localized predominantly in vascular smooth muscle cells rather than in endothelial cells and macrophages. Superoxide generation was elevated in vessels from Lepr db mice versus controls. Administration of the superoxide scavenger TEMPOL, NAD(P)H oxidase inhibitor (apocynin), or anti-TNF restored endothelium-dependent dilation in Lepr db mice. NAD(P)H oxidase activity, protein expression of nitrotyrosine, and hydrogen peroxide production were increased in Lepr db mice (compared with controls), but these variables were restored to control levels by anti-TNF. Conclusion-Advanced glycation end products/receptor of advanced glycation end products and nuclear factor-B signaling play pivotal roles in TNF expression through an increase in circulating and/or local vascular TNF production in the Lepr db mouse with type 2 diabetes. Increases in TNF expression induce activation of NAD(P)H oxidase and production of reactive oxidative species, leading to endothelial dysfunction in type 2 diabetes. (Circulation. 2007;115: 245-254.)
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 Ͼ4-fold after I/R. To determine whether TNF-␣ abrogates endothelial function after I/R, we assessed endothelial-dependent (ACh) and endothelialindependent (SNP) vasodilation. In sham controls, ACh induced dose-dependent vasodilation that was blocked by the nitric oxide synthase (NOS) inhibitor L-NMMA (10 mol/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 (O 2 ·Ϫ ) 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 O 2 ·Ϫ 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 O 2 ·Ϫ , leading to coronary endothelial dysfunction. Key Words: coronary artery disease Ⅲ endothelial function Ⅲ nitric oxide Ⅲ microcirculation Ⅲ reactive oxygen species T umor necrosis factor-␣ (TNF-␣) is an inflammatory cytokine 1 that is expressed by macrophages and cardiac tissue early during the myocardial ischemia-reperfusion (I/R) injury. 2,3 Elevations of TNF-␣ expression also appear to cause cardiomyopathy. 4,5 Interestingly, both cardiomyopathy and I/R injury are characterized by endothelial dysfunction, but, a putative role for TNF-␣ in the abnormal vasodilatory responses during I/R has not been elucidated.Studies from our laboratory 6 and others 7,8 have shown that I/R produces vascular endothelial dysfunction as defined by abrogated endothelium-dependent dilation. This adverse effect on endothelial function can occur acutely 6 or chronically (I/R injury in the pig can produce endothelial dysfunction for weeks). 9 However, endothelial dysfunction may be amplified by neutrophil-generated factors including oxygen-derived free radicals, cytokines, proteases, and lipid mediators. 10 I/R generates high levels of free radicals 11 composed of both reactive oxygen intermediates and nitric oxide (NO) via a complex sequence of events. When generated in sufficient concentrations, free radicals directly injure the myocardi...
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