S-phase kinase-associated protein-2 (Skp2) promotes vascular smooth muscle cell proliferation and neointima formation in vivo

Yih Jer Wu, Graciela B. Sala-Newby, Kuo Tung Shu, Hung I. Yeh, Keiichi Nakayama, Keiko Nakayama, Andrew C. Newby, Mark Bond

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Objective: Vascular smooth muscle cell (VSMC) proliferation plays an important role in the development of postangioplasty or in-stent restenosis, venous graft failure, and atherosclerosis. Our previous work has demonstrated S-phase kinase-associated protein-2 (Skp2), an F-box subunit of SCFSkp2 ubiquitin ligase, as an important mediator and common final pathway for growth factors, extracellular matrices, and cyclic-nucleotides to regulate VSMC proliferation in vitro. However, whether alteration of Skp2 function also regulates VSMC proliferation in vivo and neointimal thickening postvascular injury remains unclear. We investigated the effect of Skp2 on VSMC proliferation and neointimal formation in vivo. Methods and Results: Firstly, we demonstrated that Skp2-null mice developed significantly smaller neointimal areas than wild-type mice after carotid ligation. Secondly, to further identify a local rather than a systemic effect of Skp2 alteration, we demonstrated that adenovirus-mediated expression of dominant-negative Skp2 in the balloon-injured rat carotid artery significantly increased medial p27Kip1 levels, inhibited VSMC proliferation, and the subsequent neointimal thickening. Lastly, to determine if Skp2 alone is sufficient to drive VSMC proliferation and lesion development in vivo, we demonstrated that adenovirus-delivery of wild-type Skp2 to the minimally-injured rat carotids is sufficient to downregulate p27Kip1 protein levels, enhanced medial VSMC proliferation, and the neointimal thickening. Conclusion: This data provides, we believe for the first time, a more comprehensive understanding of Skp2 in the regulation of VSMC proliferation and neointimal formation and suggests that Skp2 is a promising target in the treatment of vasculoproliferative diseases.

Original languageEnglish
Pages (from-to)1135-1142
Number of pages8
JournalJournal of Vascular Surgery
Volume50
Issue number5
DOIs
Publication statusPublished - Nov 1 2009

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S-Phase Kinase-Associated Proteins
Neointima
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Proliferation
Adenoviridae
Cyclin-Dependent Kinase Inhibitor p27
Cyclic Nucleotides
Ligases
Ubiquitin
Carotid Arteries
Stents
Extracellular Matrix
Ligation
Atherosclerosis
Intercellular Signaling Peptides and Proteins

All Science Journal Classification (ASJC) codes

  • Surgery
  • Cardiology and Cardiovascular Medicine

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S-phase kinase-associated protein-2 (Skp2) promotes vascular smooth muscle cell proliferation and neointima formation in vivo. / Wu, Yih Jer; Sala-Newby, Graciela B.; Shu, Kuo Tung; Yeh, Hung I.; Nakayama, Keiichi; Nakayama, Keiko; Newby, Andrew C.; Bond, Mark.

In: Journal of Vascular Surgery, Vol. 50, No. 5, 01.11.2009, p. 1135-1142.

Research output: Contribution to journalArticle

Wu, Yih Jer ; Sala-Newby, Graciela B. ; Shu, Kuo Tung ; Yeh, Hung I. ; Nakayama, Keiichi ; Nakayama, Keiko ; Newby, Andrew C. ; Bond, Mark. / S-phase kinase-associated protein-2 (Skp2) promotes vascular smooth muscle cell proliferation and neointima formation in vivo. In: Journal of Vascular Surgery. 2009 ; Vol. 50, No. 5. pp. 1135-1142.
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T1 - S-phase kinase-associated protein-2 (Skp2) promotes vascular smooth muscle cell proliferation and neointima formation in vivo

AU - Wu, Yih Jer

AU - Sala-Newby, Graciela B.

AU - Shu, Kuo Tung

AU - Yeh, Hung I.

AU - Nakayama, Keiichi

AU - Nakayama, Keiko

AU - Newby, Andrew C.

AU - Bond, Mark

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AB - Objective: Vascular smooth muscle cell (VSMC) proliferation plays an important role in the development of postangioplasty or in-stent restenosis, venous graft failure, and atherosclerosis. Our previous work has demonstrated S-phase kinase-associated protein-2 (Skp2), an F-box subunit of SCFSkp2 ubiquitin ligase, as an important mediator and common final pathway for growth factors, extracellular matrices, and cyclic-nucleotides to regulate VSMC proliferation in vitro. However, whether alteration of Skp2 function also regulates VSMC proliferation in vivo and neointimal thickening postvascular injury remains unclear. We investigated the effect of Skp2 on VSMC proliferation and neointimal formation in vivo. Methods and Results: Firstly, we demonstrated that Skp2-null mice developed significantly smaller neointimal areas than wild-type mice after carotid ligation. Secondly, to further identify a local rather than a systemic effect of Skp2 alteration, we demonstrated that adenovirus-mediated expression of dominant-negative Skp2 in the balloon-injured rat carotid artery significantly increased medial p27Kip1 levels, inhibited VSMC proliferation, and the subsequent neointimal thickening. Lastly, to determine if Skp2 alone is sufficient to drive VSMC proliferation and lesion development in vivo, we demonstrated that adenovirus-delivery of wild-type Skp2 to the minimally-injured rat carotids is sufficient to downregulate p27Kip1 protein levels, enhanced medial VSMC proliferation, and the neointimal thickening. Conclusion: This data provides, we believe for the first time, a more comprehensive understanding of Skp2 in the regulation of VSMC proliferation and neointimal formation and suggests that Skp2 is a promising target in the treatment of vasculoproliferative diseases.

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