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(Hypertension. 2002;39:508.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Lysophosphatidylcholine Inhibits Insulin-Induced Akt Activation Through Protein Kinase C- in Vascular Smooth Muscle Cells

Evangeline D. Motley; Syeda M. Kabir; Carla D. Gardner; Kunie Eguchi; Gerald D. Frank; Toshio Kuroki; Motoi Ohba; Tadashi Yamakawa; Satoru Eguchi

From the Department of Anatomy and Physiology (E.D.M., S.M.K., C.D.G., K.E.), Meharry Medical College, and the Department of Biochemistry (G.D.F., S.E.), Vanderbilt University School of Medicine, Nashville, Tenn; the Institute of Molecular Oncology (T.K., M.O.), Showa University, Tokyo, Japan; and the Department of Endocrinology and Diabetes (T.Y.), Yokohama City University Medical Center, Yokohama, Japan.

Correspondence to Evangeline D. Motley, PhD, Department of Anatomy and Physiology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208. E-mail emotley{at}mmc.edu

Abstract— To better understand the intracellular signaling mechanism that causes the association of insulin resistance and hyperlipidemia with cardiovascular diseases, we specifically looked at the ability of lysophosphatidylcholine (lysoPC) to inhibit the Akt activation induced by insulin in cultured rat aortic vascular smooth muscle cells. LysoPC inhibited the insulin-induced phosphorylation of Akt at Ser473, and the inhibition was concentration dependent. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, inhibited the insulin-induced phosphorylation of Akt. LysoPC stimulated PKC phosphorylation at Ser660, which was inhibited by the PKC inhibitor GF109203X. The PKC-/ß-selective inhibitor Go6976 also blocked the PMA- and lysoPC-induced inhibition of Akt phosphorylation by insulin. PKC-, but not PKC-ß, is expressed in vascular smooth muscle cells, and overexpression of PKC-, but not PKC-ß or PKC-, inhibited insulin-induced Akt activation. LysoPC rapidly stimulated PKC- translocation to the membrane. In contrast, pretreatment with the p42/44 mitogen-activated protein kinase kinase inhibitor PD98059 or the p38 mitogen-activated protein kinase inhibitor SB203580 did not block the lysoPC-induced inhibition of Akt phosphorylation by insulin. In addition, lysoPC inhibited the insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 but not that of the insulin receptor ß subunit or insulin binding. PMA treatment or PKC- overexpression also inhibited the tyrosine phosphorylation of IRS-1. From these data, we conclude that lysoPC negatively regulates the insulin signal at the point of IRS-1 through PKC- in the vasculature, which may explain the association of hyperlipidemia with hyperinsulinemia in cardiovascular diseases.

Key Words: lysophosphatidylcholines • insulin resistance • muscle, smooth, vascular • protein kinases

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