Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity.
Plasma adiponectin level is significantly reduced in patients with metabolic syndrome, and vascular dysfunction is an important pathological event in these patients. However, whether adiponectin may protect endothelial cells and attenuate endothelial dysfunction caused by metabolic disorders remains largely unknown. Adult rats were fed with a regular or a high-fat diet for 14 wk. The aorta was isolated, and vascular segments were incubated with vehicle or the globular domain of adiponectin (gAd; 2 mug/ml) for 4 h. The effect of gAd on endothelial function, nitric oxide (NO) and superoxide production, nitrotyrosine formation, gp91(phox) expression, and endothelial nitric oxide synthase (eNOS)/inducible NOS (iNOS) activity/expression was determined. Severe endothelial dysfunction (maximal vasorelaxation in response to ACh: 70.3 +/- 3.3 vs. 95.2 +/- 2.5% in control, P < 0.01) was observed in hyperlipidemic aortic segments, and treatment with gAd significantly improved endothelial function (P < 0.01). Paradoxically, total NO production was significantly increased in hyperlipidemic vessels, and treatment with gAd slightly reduced, rather than increased, total NO production in these vessels. Treatment with gAd reduced (-78%, P < 0.01) superoxide production and peroxynitrite formation in hyperlipidemic vascular segments. Moreover, a moderate attenuation (-30%, P < 0.05) in gp91(phox) and iNOS overexpression in hyperlipidemic vessels was observed after gAd incubation. Treatment with gAd had no effect on eNOS expression but significantly increased eNOS phosphorylation (P < 0.01). Most noticeably, treatment with gAd significantly enhanced eNOS (+83%) but reduced iNOS (-70%, P < 0.01) activity in hyperlipidemic vessels. Collectively, these results demonstrated that adiponectin protects the endothelium against hyperlipidemic injury by multiple mechanisms, including promoting eNOS activity, inhibiting iNOS activity, preserving bioactive NO, and attenuating oxidative/nitrative stress.
Li
Rong
R
Department of Physiology, The Fourth Military Medical University, Xian, China.
Wang
Wen-Qing
WQ
Zhang
Haifeng
H
Yang
Xinchung
X
Fan
Qian
Q
Christopher
Theodore A
TA
Lopez
Bernard L
BL
Tao
Ling
L
Goldstein
Barry J
BJ
Gao
Feng
F
Ma
Xin L
XL
D000109:Acetylcholine / Q000494:pharmacology; D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004041:Dietary Fats / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D008055:Lipids / Q000097:blood; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D052242:Adiponectin; D000975:Antioxidants; D004041:Dietary Fats; D008055:Lipids; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester