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.
OBJECTIVE
Tumor necrosis factor-alpha (TNF-alpha) has been linked to obesity-related insulin resistance and impaired endothelium-dependent vasodilatation, but the mechanisms have not been elucidated. To investigate whether TNF-alpha directly impairs insulin-mediated vasoreactivity in skeletal muscle resistance arteries and the role of c-Jun N-terminal kinase (JNK) in this interference.


RESULTS
Insulin-mediated vasoreactivity of isolated resistance arteries of the rat cremaster muscle to insulin (4 to 3400 microU/mL) was studied in the absence and presence of TNF-alpha (10 ng/mL). Although insulin or TNF-alpha alone did not affect arterial diameter, insulin induced dose-dependent vasoconstriction of cremaster resistance arteries in the presence of TNF-alpha, (-12+/-1% at 272 microU/mL). Blocking endothelin receptors in the absence of TNF-alpha uncovered insulin-mediated vasodilatation (18+/-6% at 272 microU/mL) but not in the presence of TNF-alpha (2+/-2% at 272 microU/mL), showing that TNF-alpha inhibits vasodilator effects of insulin. Using digital imaging microscopy, we discovered that TNF-alpha 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-alpha, showing that JNK is required for interaction between TNF-alpha and insulin.


CONCLUSIONS
TNF-alpha inhibits vasodilator but not vasoconstrictor effects of insulin in skeletal muscle resistance arteries, resulting in insulin-mediated vasoconstriction in the presence of TNF-alpha. This effect of TNF-alpha is critically dependent on TNF-alpha-mediated activation of JNK.
Eringa
Etto C
EC
Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. e.eringa@vumc.nl
Stehouwer
Coen D A
CD
Walburg
Kimberley
K
Clark
Andrew D
AD
van Nieuw Amerongen
Geerten P
GP
Westerhof
Nico
N
Sipkema
Pieter
P
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply; D009842:Oligopeptides / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D007004:Hypoglycemic Agents; D007328:Insulin; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C076213:PD 142893; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D000109:Acetylcholine