PMID- 16322532
OWN - NLM
STAT- MEDLINE
DCOM- 20060228
LR  - 20220309
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Linking)
VI  - 26
IP  - 2
DP  - 2006 Feb
TI  - 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.
PG  - 274-80
AB  - 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. METHODS AND 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.
FAU - Eringa, Etto C
AU  - Eringa EC
AD  - Laboratory for Physiology, Institute for Cardiovascular Research, VU University 
      Medical Center, Amsterdam, The Netherlands. e.eringa@vumc.nl
FAU - Stehouwer, Coen D A
AU  - Stehouwer CD
FAU - Walburg, Kimberley
AU  - Walburg K
FAU - Clark, Andrew D
AU  - Clark AD
FAU - van Nieuw Amerongen, Geerten P
AU  - van Nieuw Amerongen GP
FAU - Westerhof, Nico
AU  - Westerhof N
FAU - Sipkema, Pieter
AU  - Sipkema P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20051201
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Endothelin-1)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Oligopeptides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vasodilator Agents)
RN  - 143037-36-9 (PD 142893)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - N9YNS0M02X (Acetylcholine)
SB  - IM
MH  - Acetylcholine/pharmacology
MH  - Animals
MH  - Arteries/drug effects/physiology
MH  - Endothelin-1/antagonists & inhibitors/metabolism
MH  - Endothelium, Vascular/drug effects/physiology
MH  - Hypoglycemic Agents/*pharmacology
MH  - Insulin/*pharmacology
MH  - JNK Mitogen-Activated Protein Kinases/*metabolism
MH  - Muscle, Skeletal/blood supply
MH  - Oligopeptides/pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Tumor Necrosis Factor-alpha/*metabolism
MH  - Vascular Resistance
MH  - Vasoconstriction/*drug effects/physiology
MH  - Vasodilation/drug effects/physiology
MH  - Vasodilator Agents/pharmacology
EDAT- 2005/12/03 09:00
MHDA- 2006/03/01 09:00
CRDT- 2005/12/03 09:00
PHST- 2005/12/03 09:00 [pubmed]
PHST- 2006/03/01 09:00 [medline]
PHST- 2005/12/03 09:00 [entrez]
AID - 01.ATV.0000198248.19391.3e [pii]
AID - 10.1161/01.ATV.0000198248.19391.3e [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2006 Feb;26(2):274-80. doi: 
      10.1161/01.ATV.0000198248.19391.3e. Epub 2005 Dec 1.