on December 1, 2005
Published online before print December 1, 2005, doi: 10.1161/01.ATV.0000198248.19391.3e
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Submitted on April 5, 2005
Accepted on September 28, 2005
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
Etto C. Eringa *;
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.
* To whom correspondence should be addressed. 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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