Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes

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• 作者：Carmela Nacci ; Valentina Leo ; Leonarda De Benedictis ; Maria A. Potenza ; Luca Sgarra ; Maria A. De Salvia ; Michael J. Quon ; Monica Montagnani ; ^{monica.montagnani@uniba.it}
• 关键词：Perivascular adipose tissue (PVAT) ; Adiponectin (Ad) ; Type1 diabetes mellitus (T1DM) ; Infliximab
• 刊名：Vascular Pharmacology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：87
• 期：Complete
• 页码：83-91
• 全文大小：1001 K
• 卷排序：87

文摘

Increased TNFα-mediated JNK signaling in the perivascular adipose tissue (PVAT) may contribute to the pathogenesis of vascular complications in T1DM by reducing adiponectin (Ad) synthesis and therefore impairing Ad-mediated activity in the contiguous blood vessel system.We evaluated whether in vivo treatment with the TNFα blocking antibody infliximab normalized expression of Ad and Ad receptors in various fat depots, and whether this effect correlated with improved endothelial activity and vasodilator function in streptozotocin (STZ)-induced diabetic mice. STZ mice were studied at 1 and 2 weeks after diabetes onset, and compared to age-matched infliximab-treated diabetic (I-STZ) and control animals (CTRL) (n = 10 each group). In STZ mice, activation of pro-inflammatory JNK signaling was faster in PVAT (P < 0.01) than in visceral (VAT), epididymal (EAT) and subcutaneous (SAT) adipose depots, and associated with decreased Ad synthesis and dysregulated AdipoR1/R2 levels. In parallel, activation of JNK in aortic endothelial cells and mesenteric arteries was associated with decreased expression/phosphorylation of eNOS and impaired ACh-mediated vasodilation (P < 0.05 vs. CTRL). Treatment with infliximab abrogated JNK activation, ameliorated Ad protein expression, and normalized expression of both AdipoR1 and AdipoR2 in PVAT, concomitantly improving eNOS expression and vessel relaxation in mesenteric arteries from I-STZ mice (P < 0.01 vs. STZ).These observations underline the early susceptibility of PVAT to activation of pro-inflammatory JNK signaling, and highlight its potential importance in early vascular changes of T1DM. Further elucidation of the role of PVAT in cardiovascular complications may allow for the design of novel therapeutic strategies directly addressing PVAT pathophysiology.