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Physiological concentrations of insulin induce endothelin-dependent vasoconstriction of skeletal muscle resistance arteries in the presence of tumor necrosis factor-alpha dependence on c-jun N-terminal kinase

Citation

Eringa, EC and Stehouwer, CDA and Walburg, K and Clark, ADH and van Nieuw Amerongen, GP and Westerhof, N and Sipkema, P, Physiological concentrations of insulin induce endothelin-dependent vasoconstriction of skeletal muscle resistance arteries in the presence of tumor necrosis factor-alpha dependence on c-jun N-terminal kinase, Arteriosclerosis, Thrombosis, and Vascular Biology, 26, (2) pp. 274-280. ISSN 1079-5642 (2006) [Refereed Article]

DOI: doi:10.1161/01.ATV.0000198248.19391.3e

Abstract

Objective - Tumor necrosis factor-α (TNF-α) has been linked to obesity-related insulin resistance and impaired endothelium-dependent vasodilatation, but the mechanisms have not been elucidated. To investigate whether TNF-α 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-α (10 ng/mL). Although insulin or TNF-α alone did not affect arterial diameter, insulin induced dose-dependent vasoconstriction of cremaster resistance arteries in the presence of TNF-α, (-12±1% at 272 μU/mL). Blocking endothelin receptors in the absence of TNF-α uncovered insulin-mediated vasodilatation (18±6% at 272 μU/mL) but not in the presence of TNF-α (2±2% at 272 μU/mL), showing that TNF-α inhibits vasodilator effects of insulin. Using digital imaging microscopy, we discovered that TNF-α 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-α, showing that JNK is required for interaction between TNF-α and insulin. Conclusions - TNF-α inhibits vasodilator but not vasoconstrictor effects of insulin in skeletal muscle resistance arteries, resulting in insulin-mediated vasoconstriction in the presence of TNF-α. This effect of TNF-α is critically dependent on TNF-α-mediated activation of JNK. © 2006 American Heart Association, Inc.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Endocrinology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Diabetes
Author:Clark, ADH (Mr Andrew Clark)
ID Code:41920
Year Published:2006
Web of Science® Times Cited:49
Deposited By:Biochemistry
Deposited On:2006-08-01
Last Modified:2011-09-21
Downloads:0

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