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.
|Number of pages||7|
|Journal||Arteriosclerosis, Thrombosis, and Vascular Biology|
|Publication status||Published - 1 Feb 2006|