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 whethe...

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Bibliographic Details
Published in:Vascular pharmacology 2016-12, Vol.87, p.83-91
Main Authors: Nacci, Carmela, Leo, Valentina, De Benedictis, Leonarda, Potenza, Maria A, Sgarra, Luca, De Salvia, Maria A, Quon, Michael J, Montagnani, Monica
Format: Article
Language:English
Subjects:
Activation
Adiponectin
Adiponectin (Ad)
Adiponectin - genetics
Adiponectin - metabolism
Adipose tissue
Adipose Tissue - drug effects
Adipose Tissue - metabolism
Animals
Aorta
Arteries
Blocking antibodies
Blood vessels
Cardiovascular
Cardiovascular disease
Cells, Cultured
Complications
Diabetes
Diabetes mellitus
Diabetes mellitus (insulin dependent)
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - physiopathology
Diabetes Mellitus, Type 1 - drug therapy
Diabetes Mellitus, Type 1 - physiopathology
Endothelial cells
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Humans
Immunotherapy
Inflammation
Infliximab
Infliximab - pharmacology
Male
MAP Kinase Signaling System - drug effects
Mesenteric Arteries - metabolism
Mice
Mice, Inbred BALB C
Monoclonal antibodies
Nitric oxide
Nitric Oxide - metabolism
Nitric Oxide Synthase Type III - genetics
Nitric Oxide Synthase Type III - metabolism
Pathogenesis
Perivascular adipose tissue (PVAT)
Phosphorylation
Protein expression
Proteins
Receptors
Receptors, Adiponectin - genetics
Receptors, Adiponectin - metabolism
Signaling
Streptozocin
Synthesis
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor necrosis factor-α
Type1 diabetes mellitus (T1DM)
Vasodilation
Vasodilation - drug effects
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Summary: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 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.
ISSN:1537-1891
1879-3649
DOI:10.1016/j.vph.2016.08.007