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(Circulation Research. 2006;99:69.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Tumor Necrosis Factor- Induces Endothelial Dysfunction in the Prediabetic Metabolic Syndrome

Andrea Picchi^*, Xue Gao^*, Souad Belmadani^*, Barry J. Potter, Marta Focardi, William M. Chilian, Cuihua Zhang

From the Departments of Anesthesiology (A.P., X.G., C.Z.), Surgery (A.P., X.G., C.Z.), and Physiology (A.P., X.G., S.B., B.J.P., M.F., W.M.C., C.Z.), Louisiana State University Health Sciences Center, New Orleans. Current address for C.Z.: Veterinary Physiology & Pharmacology, Texas A&M University, College Station.

Correspondence to Cuihua Zhang, MD, PhD, Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX 77843-4466. E-mail czhang{at}cvm.tamu.edu

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 (O₂·^–) generation was elevated in vessels from ZOF rats compared with lean rats, and administration of the O₂·^– 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 O₂·^–.

Key Words: coronary microcirculation • endothelial dysfunction • inflammation • metabolic syndrome • superoxide

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