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

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)742-747
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume25
Issue number4
DOIs
StatePublished - Apr 1 2005

Keywords

  • Forkhead transcription factors
  • Neointima
  • Vascular smooth muscle cell
  • p27

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Park, K. W., Kim, D. H., You, H. J., Sir, J. J., Jeon, S. I., Youn, S. W., Yang, H. M., Skurk, C., Park, Y. B., Walsh, K., & Kim, H. S. (2005). Activated forkhead transcription factor inhibits neointimal hyperplasia after angioplasty through induction of p27. Arteriosclerosis, thrombosis, and vascular biology, 25(4), 742-747. https://doi.org/10.1161/01.ATV.0000156288.70849.26