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

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 TNFdirectly 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 U/mL) was studied in the absence and presence of TNF(10 ng/mL). Although insulin or TNFalone did not affect arterial diameter, insulin induced dose-dependent vasoconstriction of cremaster resistance arteries in the presence of TNF, ( 12 1% at 272 U/mL). Blocking endothelin receptors in the absence of TNFuncovered insulin-mediated vasodilatation (18 6% at 272 U/mL) but not in the presence of TNF(2 2% at 272 U/mL), showing that TNFinhibits vasodilator effects of insulin. Using digital imaging microscopy, we discovered that TNFactivates 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 TNFand insulin. Conclusions—TNFinhibits 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 TNFis critically dependent on TNF–mediated activation of JNK. (Arterioscler Thromb Vasc Biol. 2006;26:000-000.)