Published Online
on January 13, 2003

A more recent version of this article appeared on March 1, 2003

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Submitted on September 19, 2002
Revised on November 12, 2002

Insulin-Induced Akt Activation Is Inhibited by Angiotensin II in the Vasculature Through Protein Kinase C-

Evangeline D. Motley^*; Kunie Eguchi; Carla Gardner; Adrienne L. Hicks; Cherilynn M. Reynolds; Gerald D. Frank; Mizuo Mifune; Motoi Ohba; and Satoru Eguchi

From the Department of Anatomy and Physiology, Meharry Medical College (E.D.M., K.E., C.G., A.L.H., C.M.R.), Nashville, Tenn; the Department of Biochemistry, Vanderbilt University School of Medicine (K.E., G.D.F., M.M., S.E.), Nashville, Tenn; and Institute of Molecular Oncology, Showa University (M.O.), Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: emotley{at}mmc.edu.

Abstract--Insulin resistance is an important risk factor in the development of cardiovascular diseases such as hypertension and atherosclerosis. However, the specific role of insulin resistance in the etiology of these diseases is poorly understood. Angiotensin (Ang) II is a potent vasculotrophic and vasoconstricting factor. We hypothesize that in vascular smooth muscle cells (VSMCs), Ang II interferes with insulin action by inhibiting Akt, a major signaling molecule implicated in the biological actions of insulin. By immunoblotting with a phospho-specific antibody for Akt, we found that Ang II inhibits insulin-induced Akt phosphorylation in a time- and concentration-dependent manner. The inhibitory effect of Ang II was blocked by a Ang II type 1 receptor antagonist, RNH6270. A protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate, also inhibited insulin-induced Akt phosphorylation. PKC inhibitors, including Go6976 (specific for - and -isoforms), blocked the Ang II- and PMA-induced inhibition of Akt phosphorylation by insulin. Moreover, overexpression of PKC- but not PKC- isoform by adenovirus inhibited insulin-induced Akt phosphorylation. By contrast, an epidermal growth factor receptor inhibitor (AG1478), a p42/44 mitogen-activated protein kinase (MAPK) kinase inhibitor (PD 598,059), and a p38 MAPK inhibitor (SB 203,580) did not block the Ang II-induced inhibition of Akt phosphorylation. From these data, we conclude that Ang II negatively regulates the insulin signal, Akt, in the vasculature specifically through PKC- activation, providing an alternative molecular mechanism that may explain the association of hyperinsulinemia with cardiovascular diseases.

Key words: angiotensin II • insulin • protein kinases • Akt • muscle, vascular, smooth

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