This Article Full Text Full Text (PDF) All Versions of this Article: 25/4/742    most recent 01.ATV.0000156288.70849.26v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Park, K.-W. Articles by Kim, H.-S. Search for Related Content PubMed PubMed Citation Articles by Park, K.-W. Articles by Kim, H.-S. Related Collections Restenosis Smooth muscle proliferation and differentiation Gene therapy

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:742.)
© 2005 American Heart Association, Inc.

Vascular Biology

Activated Forkhead Transcription Factor Inhibits Neointimal Hyperplasia After Angioplasty Through Induction of p27

Kyung-Woo Park; Dae-Hee Kim; Hyun-Jung You; Jung-Ju Sir; Soo-In Jeon; Seock-Won Youn; Han-Mo Yang; Carsten Skurk; Young-Bae Park; Kenneth Walsh; Hyo-Soo Kim

From Cardiovascular Laboratory (K.-W.P., D.-H.K., H.-J.Y., J.-J.S., S.-I.J., S.-W.Y., H.-M.Y., Y.-B.P., H.-S.K.), Clinical Research Institute, Seoul National University Hospital; Whitaker Cardiovascular Institute (C.S., K.W.), Boston University School of Medicine, Boston, Mass; Department of Internal Medicine (J.-J.S., Y.-B.P., H.-S.K.), Seoul National University College of Medicine, Seoul, Korea.

Correspondence to Hyo-Soo Kim, MD, PhD, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea. E-mail hyosoo{at}snu.ac.kr

Objective— We examined the effects of FKHRL1 (forkhead transcription factor in rhabdomyosarcoma like-1) overexpression on vascular smooth muscle cell (VSMC) proliferation, apoptosis, and cell cycle, in vitro, and the role of FKHRL1 and p27 in the pathophysiology of neointimal growth after balloon angioplasty, in vivo. Furthermore, we tested whether FKHRL1 overexpression can inhibit neointimal hyperplasia in a rat carotid artery model.

Methods and Results— Adenovirus expressing the constitutively active FKHRL1 (FKHRL1-TM; triple mutant) with 3 Akt phosphorylation sites mutated was transfected to subconfluent VSMCs. FKHRL1 overexpression in cultured VSMCs increased p27 expression, leading to G1 phase cell-cycle arrest and increased apoptosis. In vivo, the phosphorylation of FKHRL1 increased significantly 3 hours after balloon injury and decreased thereafter, with the subsequent downregulation of p27. Although the phosphorylation of FKHRL1 was greatest at 3 hours, the downregulation of p27 showed a temporal delay, only slightly starting to decrease after 3 hours and reaching a nadir at 72 hours after balloon injury. Gene transfer of FKHRL1-TM increased p27, decreased proliferation, and increased apoptosis of VSMCs, which resulted in a marked reduction in neointima formation (intima-to-media ratio: 0.31±0.13 versus 1.17±0.28, for FKHRL1-TM versus Adv-GFP; P<0.001).

Conclusion— Balloon angioplasty leads to the phosphorylation of FKHRL1 and decreased expression of p27, thereby promoting a proliferative phenotype in VSMCs in vitro and in vivo. This study reveals the importance of FKHRL1 in proliferation and viability of VSMCs and suggests that it may serve as a molecular target for interventions to reduce neointima formation after angioplasty.

The role of FKHRL1 (forkhead transcription factor in rhabdomyosarcoma like-1) in VSMC biology and in neointimal hyperplasia after balloon angioplasty has not been studied. Here, we show that the inactivation of the forkhead transcription factor is required for neointimal hyperplasia after angioplasty, and that overexpression of FKHRL1 leads to the induction of p27 resulting in inhibition of neointimal hyperplasia.

Key Words: forkhead transcription factors • neointima • p27 • vascular smooth muscle cell

This article has been cited by other articles:

				J.-Y. Kim, H.-J. Cho, J.-J. Sir, B.-K. Kim, J. Hur, S.-W. Youn, H.-M. Yang, S.-I. Jun, K.-W. Park, S.-J. Hwang, et al. Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia Cardiovasc Res, June 1, 2009; 82(3): 550 - 560. [Abstract] [Full Text] [PDF]

				D. Allard, N. Figg, M. R. Bennett, and T. D. Littlewood Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3 J. Biol. Chem., July 11, 2008; 283(28): 19739 - 19747. [Abstract] [Full Text] [PDF]

				H.-Y. Lee, H.-J. You, J.-Y. Won, S.-W. Youn, H.-J. Cho, K.-W. Park, W.-Y. Park, J.-S. Seo, Y.-B. Park, K. Walsh, et al. Forkhead Factor, FOXO3a, Induces Apoptosis of Endothelial Cells Through Activation of Matrix Metalloproteinases Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 302 - 308. [Abstract] [Full Text] [PDF]

				K. N. Papanicolaou, Y. Izumiya, and K. Walsh Forkhead Transcription Factors and Cardiovascular Biology Circ. Res., January 4, 2008; 102(1): 16 - 31. [Abstract] [Full Text] [PDF]

				K. Nakamura, S.-i. Yamagishi, T. Matsui, T. Yoshida, K. Takenaka, Y. Jinnouchi, Y. Yoshida, S.-i. Ueda, H. Adachi, and T. Imaizumi Pigment Epithelium-Derived Factor Inhibits Neointimal Hyperplasia after Vascular Injury by Blocking NADPH Oxidase-Mediated Reactive Oxygen Species Generation Am. J. Pathol., June 1, 2007; 170(6): 2159 - 2170. [Abstract] [Full Text] [PDF]

				T. D. Littlewood and M. R. Bennett Foxing Smooth Muscle Cells: FOXO3a-CYR61 Connection Circ. Res., February 16, 2007; 100(3): 302 - 304. [Full Text] [PDF]

				H.-Y. Lee, J.-W. Chung, S.-W. Youn, J.-Y. Kim, K.-W. Park, B.-K. Koo, B.-H. Oh, Y.-B. Park, B. Chaqour, K. Walsh, et al. Forkhead Transcription Factor FOXO3a Is a Negative Regulator of Angiogenic Immediate Early Gene CYR61, Leading to Inhibition of Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia Circ. Res., February 16, 2007; 100(3): 372 - 380. [Abstract] [Full Text] [PDF]

				F. Li, C. Zhang, S. Schaefer, A. Estes, and K. U. Malik ANG II-induced neointimal growth is mediated via cPLA2- and PLD2-activated Akt in balloon-injured rat carotid artery Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2592 - H2601. [Abstract] [Full Text] [PDF]

				Md. R. Abid, K. Yano, S. Guo, V. I. Patel, G. Shrikhande, K. C. Spokes, C. Ferran, and W. C. Aird Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia J. Biol. Chem., August 19, 2005; 280(33): 29864 - 29873. [Abstract] [Full Text] [PDF]