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J. Biol. Chem., Vol. 282, Issue 49, 36112-36120, December 7, 2007

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Rapamycin Promotes Vascular Smooth Muscle Cell Differentiation through Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase/Akt2 Feedback Signaling^*

Kathleen A. Martin¹², Bethany L. Merenick¹, Min Ding, Kristina M. Fetalvero, Eva M. Rzucidlo, Courtney D. Kozul, David J. Brown, Helen Y. Chiu, Maureen Shyu, Bethany L. Drapeau, Robert J. Wagner, and Richard J. Powell

From the Division of Vascular Surgery and Department of Pharmacology and Toxicology, Dartmouth Medical School, Lebanon, New Hampshire 03756

The phenotypic plasticity of mature vascular smooth muscle cells (VSMCs) facilitates angiogenesis and wound healing, but VSCM dedifferentiation also contributes to vascular pathologies such as intimal hyperplasia. Insulin/insulin-like growth factor I (IGF-I) is unique among growth factors in promoting VSMC differentiation via preferential activation of phosphatidylinositol 3-kinase (PI3K) and Akt. We have previously reported that rapamycin promotes VSMC differentiation by inhibiting the mammalian target of rapamycin (mTOR) target S6K1. Here, we show that rapamycin activates Akt and induces contractile protein expression in human VSMC in an insulin-like growth factor I-dependent manner, by relieving S6K1-dependent negative regulation of insulin receptor substrate-1 (IRS-1). In skeletal muscle and adipocytes, rapamycin relieves mTOR/S6K1-dependent inhibitory phosphorylation of IRS-1, thus preventing IRS-1 degradation and enhancing PI3K activation. We report that this mechanism is functional in VSMCs and crucial for rapamycin-induced differentiation. Rapamycin inhibits S6K1-dependent IRS-1 serine phosphorylation, increases IRS-1 protein levels, and promotes association of tyrosine-phosphorylated IRS-1 with PI3K. A rapamycin-resistant S6K1 mutant prevents rapamycin-induced Akt activation and VSMC differentiation. Notably, we find that rapamycin selectively activates only the Akt2 isoform and that Akt2, but not Akt1, is sufficient to induce contractile protein expression. Akt2 is required for rapamycin-induced VSMC differentiation, whereas Akt1 appears to oppose contractile protein expression. The anti-restenotic effect of rapamycin in patients may be attributable to this unique pattern of PI3K effector regulation wherein anti-differentiation signals from S6K1 are inhibited, but pro-differentiation Akt2 activity is promoted through an IRS-1 feedback signaling mechanism.

Received for publication, May 11, 2007 , and in revised form, September 21, 2007.

^* This work was supported by grants from the Hitchcock Foundation and American Heart Association Scientist Development Grant 0230356N (to K. A. M.), NCI Training Grant CA09658 from the National Institutes of Health (to K. M. F.), the Lifeline Foundation (to H. Y. C.), National Institutes of Health Grant 5KO8HL71905-3 (to E. M. R.), and NHLBI Grant R01 HL76612 from the National Institutes of Health (to R. J. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Vascular Surgery, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756. Tel.: 603-650-7439; Fax: 603-650-4928; E-mail: Kathleen.A.Martin{at}Dartmouth.edu.

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