Resistin impairs insulin-evoked vasodilation.
OBJECTIVE
Since vascular dysfunction is a main trait of obese subjects, in the present study we evaluated the vascular impact of resistin, a recently discovered hormone markedly increased in obesity.


METHODS
We performed our analysis on aortic and mesenteric segments from young and old C57BL/6 mice and on cultured endothelial cells. Resistin-induced vascular effect was evaluated in vitro and in vivo. Molecular analyses were performed by immunoprecipitation and Western blotting.


RESULTS
Recombinant murine resistin did not induce changes in either basal vascular tone or phenylephrine-induced vascular contraction. In contrast, both in vivo and in vitro administration of resistin significantly impaired dose-dependent insulin-evoked vasodilation by reducing endothelial nitric oxide synthase (eNOS) enzymatic activity. This effect of resistin was selective for insulin vascular action, since vasodilatation induced by increasing doses of acetylcholine or nitroglycerin was not influenced by the hormone. Molecular analysis of endothelial cells further detailed resistin-induced vascular resistance by showing impairment of insulin-evoked AKT and eNOS phosphorylations after exposure to resistin. Even this latter abnormality is selective of insulin signaling since AKT/eNOS phosphorylations are normally activated during acetylcholine stimulation. More important, the resistin-induced endothelial dysfunction depends on resistin's ability to alter insulin receptor substrate (IRS)-1 tyrosine/serine phosphorylation and its consequent interaction with phosphatidylinositol 3-kinase.


CONCLUSIONS
Our results demonstrate that resistin is able to induce a selective vascular insulin resistance-impairing endothelial IRS-1 signaling pathway that leads to eNOS activation and vasodilation.
Department of Angio-Cardio-Neurology, Neuromed Institute, Pozzilli, Italy.
Maria Teresa
MT
Gentile
Carmine
C
Vecchione
Gennaro
G
Marino
Alessandra
A
Aretini
Alba
A
Di Pardo
Giovanna
G
Antenucci
Angelo
A
Maffei
Giuseppe
G
Cifelli
Luca
L
Iorio
Alessandro
A
Landolfi
Giacomo
G
Frati
Giuseppe
G
Lembo
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000375:Aging; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D052243:Resistin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D052243:Resistin; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt