Published online before print December 1, 2005, doi: 10.1161/01.ATV.0000198248.19391.3e
© 2006 American Heart Association, Inc.
Vascular Biology |
Physiological Concentrations of Insulin Induce Endothelin-Dependent Vasoconstriction of Skeletal Muscle Resistance Arteries in the Presence of Tumor Necrosis Factor-
Dependence on c-Jun N-Terminal Kinase
From the Laboratory for Physiology (E.C.E., K.W., G.P.vNA., N.W., P.S.), Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands; Department of Internal Medicine (C.D.A.S.), Academic Hospital Maastricht, The Netherlands; and Division of Biochemistry (A.D.C.), Medical School, University of Tasmania, Hobart, Australia.
Correspondence to Etto C. Eringa, PhD, Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail e.eringa{at}vumc.nl
Objective— Tumor necrosis factor-
(TNF-) has been linked to obesity-related insulin resistance and impaired endothelium-dependent vasodilatation, but the mechanisms have not been elucidated. To investigate whether TNF- directly impairs insulin-mediated vasoreactivity in skeletal muscle resistance arteries and the role of c-Jun N-terminal kinase (JNK) in this interference.
Methods and Results— Insulin-mediated vasoreactivity of isolated resistance arteries of the rat cremaster muscle to insulin (4 to 3400 µU/mL) was studied in the absence and presence of TNF- (10 ng/mL). Although insulin or TNF- alone did not affect arterial diameter, insulin induced dose-dependent vasoconstriction of cremaster resistance arteries in the presence of TNF-, (–12±1% at 272 µU/mL). Blocking endothelin receptors in the absence of TNF- uncovered insulin-mediated vasodilatation (18±6% at 272 µU/mL) but not in the presence of TNF- (2±2% at 272 µU/mL), showing that TNF- inhibits vasodilator effects of insulin. Using digital imaging microscopy, we discovered that TNF- activates JNK in arterial endothelium, visible as an increase in phosphorylated JNK. Moreover, inhibition of JNK with the cell-permeable peptide inhibitor L-JNKI abolished insulin-mediated vasoconstriction in the presence of TNF-, showing that JNK is required for interaction between TNF- and insulin.
Conclusions— TNF- inhibits vasodilator but not vasoconstrictor effects of insulin in skeletal muscle resistance arteries, resulting in insulin-mediated vasoconstriction in the presence of TNF-. This effect of TNF- is critically dependent on TNF-–mediated activation of JNK.
Key Words: cytokines • endothelin • endothelium • insulin resistance • microcirculation • vascular biology
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