Reactive oxygen species induced by diamide inhibit insulin-induced ATP-sensitive potassium channel activation in cultured vascular smooth muscle cells.
Both insulin resistance and reactive oxygen species (ROS) have been reported to play essential pathophysiological roles in cardiovascular diseases. However, the mechanistic link between ROS and insulin resistance in the vasculature remains unclear. Recently we have shown that insulin causes KATP channel activation mediated by PI3K in cultured vascular smooth muscle cells (VSMCs). KATP channel in VSMCs is critical in the regulation of vascular tonus. Here we examined the effects of ROS induced by a thol-oxidizing agent, diamide, on the insulin signalling pathway and KATP channel activities in cultured VSMCs (A10 cells). Diamide (100 microM) increased intercellular ROS and extracellular signal-regulated kinases (ERK) activity. Treatment with 100 M diamide suppressed significantly insulin-induced IRS and Akt phosphorylation. In addition to IRS and Akt, diamide inhibited insulin receptor auto-phosphorylation. Patch-clamp study showed that diamide suppressed insulin-induced but did not pinacidil-induced KATP channel activities in A10 cells. From these data, we conclude that ROS inhibit critical insulin signal transduction components including IRS and Akt, and these effects cause down-regulation of insulin's action in the vasculature including KATP channel activation. This study may contribute to our understanding of mechanisms of insulin resistance-associated cardiovascular disease.
Mawatari
Kazuaki
K
Department of Metabolism and Nutrition, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Yasui
Sonoko
S
Morizumi
Ran
R
Hamamoto
Akiko
A
Furukawa
Hiroko
H
Koyama
Kei
K
Hattori
Atsushi
A
Yoshioka
Emiko
E
Yoshida
Masaki
M
Nakano
Masayuki
M
Teshigawara
Kiyoshi
K
Harada
Nagakatsu
N
Hosaka
Toshio
T
Takahashi
Akira
A
Nakaya
Yutaka
Y
D000818:Animals; D002478:Cells, Cultured; D003958:Diamide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D007333:Insulin Resistance; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D015221:Potassium Channels / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
D015221:Potassium Channels; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D003958:Diamide; D011972:Receptor, Insulin