Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome.
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-alpha 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-alpha restored endothelium-dependent dilation in the ZOF rats. Real-time PCR and Western blotting revealed that mRNA and protein of TNF-alpha 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-alpha 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-alpha 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-alpha and subsequent production of O2*-.
Picchi
Andrea
A
Departmentof Anesthesiology, Louisiana State University Health Sciences Center, New Orleans, USA.
Gao
Xue
X
Belmadani
Souad
S
Potter
Barry J
BJ
Focardi
Marta
M
Chilian
William M
WM
Zhang
Cuihua
C
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000503:physiopathology; D009994:Osmolar Concentration; D011236:Prediabetic State / Q000097:blood / Q000503:physiopathology*; D012333:RNA, Messenger / Q000097:blood; D051381:Rats; D011924:Rats, Zucker; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D000109:Acetylcholine