title: Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes.
abstract: 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 2weeks 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.
authors: Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy.
authors: Carmela
authors: C
authors: Nacci
authors: Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy.
authors: Valentina
authors: V
authors: Leo
authors: Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy.
authors: Leonarda
authors: L
authors: De Benedictis
authors: Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy.
authors: Maria A
authors: MA
authors: Potenza
authors: Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy.
authors: Luca
authors: L
authors: Sgarra
authors: Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy.
authors: Maria A
authors: MA
authors: De Salvia
authors: Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy.
authors: Michael J
authors: MJ
authors: Quon
authors: Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy. Electronic address: monica.montagnani@uniba.it.
authors: Monica
authors: M
authors: Montagnani
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000069285:Infliximab / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D052242:Adiponectin; D054419:Receptors, Adiponectin; D014409:Tumor Necrosis Factor-alpha; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D009569:Nitric Oxide; D013311:Streptozocin; D000069285:Infliximab; D052250:Nitric Oxide Synthase Type III
keywords: Adiponectin (Ad); Infliximab; Perivascular adipose tissue (PVAT); Type1 diabetes mellitus (T1DM)