Vascular Generation of Tumor Necrosis Factor-α Reduces Nitric Oxide Availability in Small Arteries From Visceral Fat of Obese Patients

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• 作者：Agostino Virdis MD ; ^{agostino.virdis@med.unipi.it"" rel=""nofollow} ; Ferruccio Santini MD^† ; ; Rocchina Colucci PhD ; Emiliano Duranti BiolD ; Guido Salvetti MD^† ; ; Ilaria Rugani BiolD ; Cristina Segnani BiolD^‡ ; ; Marco Anselmino MD^§ ; ; Nunzia Bernardini MD^‡ ; ; Corrado Blandizzi MD ; Antonio Salvetti MD ; Aldo Pinchera MD^† ; ; Stefano Taddei MD
• 关键词：inflammation ; nitric oxide ; obesity ; reactive oxygen species ; small vessels
• 刊名：Journal of the American College of Cardiology
• 出版年：2011
• 出版时间：12 July 2011
• 年：2011
• 卷：58
• 期：3
• 页码：238-247
• 全文大小：1602 K

文摘

Objectives

The aim of this study was to assess whether small arteries from visceral fat of obese patients show a reduced nitric oxide (NO)-dependent relaxation, as compared with lean control subjects, focusing on the role of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α.

Background

Visceral obesity is characterized by endothelial dysfunction.

Methods

Small arteries from 14 obese (body mass index 48.4 ± 11 kg/m²) and 14 control subjects (body mass index 24.9 ± 2 kg/m²), dissected after a visceral fat biopsy (laparoscopy), were evaluated on a pressurized micromyograph. Endothelium-dependent relaxation was assessed by acetylcholine. The NO availability, superoxide production, and inflammation were assessed by testing acetylcholine under the nitric oxide synthase (NOS) inhibitor N^ω-nitro-L-arginine methylester, tempol (superoxide scavenger), and infliximab (monoclonal anti–TNF-α antibody), respectively. The roles of nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase (iNOS) were assessed by their selective inhibitors apocynin and S-methylisothiourea (SMT), respectively. Vascular superoxide generation (dihydroethidium staining) protein expression of TNF-α and NOS isoforms (Western Blot) and TNF-α localization (immunohistochemistry) were assessed.

Results

Vessels from obese patients displayed a blunted relaxation to acetylcholine and a reduced inhibitory effect of N^ω-nitro-L-arginine methylester. These alterations were normalized by tempol or infliximab while being partly ameliorated by apocynin and SMT. Vascular superoxide generation was increased (p < 0.01) in obese patients. This condition was abrogated by both tempol and infliximab and partly (p < 0.05 vs. control subjects) reduced by apocynin or SMT. Enhanced TNF-α and iNOS expression together with increased TNF-α localization in the vascular media were detected.

Conclusions

Small arteries from visceral fat of obese patients are characterized by an increased TNF-α production, which reduces NO availability by promoting superoxide generation via nicotinamide adenine dinucleotide phosphate oxidase and iNOS activation.