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(Circulation Research. 1996;79:1167-1176.)
© 1996 American Heart Association, Inc.

Articles

Insulin Signaling and Its Regulation of System A Amino Acid Uptake in Cultured Rat Vascular Smooth Muscle Cells

Toshiyuki Obata, Atsunori Kashiwagi, Hiroshi Maegawa, Yoshihiko Nishio, Satoshi Ugi, Hideki Hidaka, Ryuichi Kikkawa

the Third Department of Medicine, Shiga University of Medical Science, Otsu, Japan.

Correspondence to Atsunori Kashiwagi, MD, PhD, the Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-21, Japan. E-mail kasiwagi@belle.shiga-med.ac.jp.

Hyperinsulinemia has been recognized as an independent risk factor for atherosclerosis. However, its exact mechanisms are still unclear. In our previous work, we showed that 10 nmol/L insulin stimulated neither mitogen-activated protein kinase (MAP kinase) activity nor [³H]thymidine incorporation but did stimulate S6 kinase through the specific insulin receptors in cultured rat vascular smooth muscle cells (VSMCs). In this study, we observed that 1 nmol/L insulin stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and activated IRS-1–dependent phosphatidylinositol 3'-kinase (PI 3'-kinase) and p70 S6 kinase (p70^S6K) but not MAP kinase (extracellular signal-regulated kinase 2) and p90 S6 kinase (p90^RSK). However, 10 nmol/L insulin-like growth factor I stimulated all these pathways. Finally, 10 nmol/L insulin stimulated -aminoisobutyric acid (AIB) uptake, and wortmannin (100 nmol/L) completely inhibited insulin-stimulated AIB uptake, whereas rapamycin (20 nmol/L) had no such effect. Furthermore, cycloheximide (10 µg/mL) completely inhibited insulin-stimulated AIB uptake, but actinomycin D (5 µg/mL) failed to inhibit this. Thus, we reached the following conclusions: (1) Insulin (1 nmol/L) induced phosphorylation of IRS-1 and activated the PI 3'-kinase and p70^S6K pathways in VSMCs, even though 10 nmol/L insulin did not significantly stimulate MAP kinase or p90^RSK. (2) Stimulation of AIB uptake by insulin was regulated at the translational level via wortmannin-sensitive pathways but not p70^S6K pathways.

Key Words: insulin • wortmannin • -aminoisobutyric acid • vascular smooth muscle cell

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