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Upregulation of TNF-alpha and Receptors Contribute to Endothelial Dysfunction in Zucker Diabetic Rats

Departments of Internal Medicine, Medical Pharmacology & Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211

 *Corresponding author

Cuihua Zhang, MD, PhD

Departments of Internal Medicine, Medical

Pharmacology & Physiology and Nutritional Sciences

Dalton Cardiovascular Research Center

University of Missouri

Columbia, MO 65211

Phone: 573-882-2427 (O); 573-884-6208 (Lab)

Fax: 573-884-4232

E-mail address: ZhangCu@missouri.edu

Abstract

Diabetes mellitus is a major risk factor to impair endothelial function and induce cardiovascular diseases. TNF-alpha (TNF) is expressed during a variety of inflammatory conditions. We hypothesized that impairment in coronary endothelial function in type 2 diabetes is due to the overexpression of TNF and TNF receptors (TNFRs). Endothelium-dependent (acetylcholine, ACh) and -independent vasodilation (sodium nitroprusside, SNP) of isolated, pressurized (60 cmH₂O) coronary arteries (50-100 µm) from lean control and Zucker diabetic fatty (ZDF, the model of type 2 diabetes) rats were determined. In lean rats, SNP and ACh induced dose-dependent vasodilation, but dilation to only ACh was blocked by the NOS inhibitor N^G-monomethyl-L-arginine (L-NMMA, 10 µM). In ZDF rats, dilation to ACh was blunted compared to lean rats, but SNP-induced dilation was comparable. Neutralizing antibodies to TNF, or blockade of NAD(P)H and xanthine oxidase, partially restored endothelium-dependent, NO-mediated vasodilation in isolated coronary arteries in ZDF rats, but anti-TNF did not alter endothelium-dependent vasodilation in lean rats. The mRNA expression of TNF receptor 1 (TNFR1, but not TNFR2) significantly increased in coronary arteries in ZDF rats. Protein expression of TNF and N-Tyr (ONOO¯) were higher in coronary arteries in ZDF than those in lean rats. Production of H₂O_2, NAD(P)H oxidase and  xanthine oxidase activity were all higher in ZDF rats than those in lean controls; anti-TNF reduces the production of H₂O₂, N-Tyr expression, NAD(P)H oxidase and xanthine oxidase activity in ZDF rats. These results demonstrate the endothelial dysfunction occurring in type 2 diabetes is the result of effects of the inflammatory cytokine TNF that activates NAD(P)H oxidase and xanthine oxidase; and perhaps acts mainly through the overexpression of TNFR1.

Keywords:  Microcirculation, coronary artery disease, nitric oxide.

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