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


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 p27(Kip1) 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 p27(Kip1) protein levels, enhanced medial VSMC proliferation, and the neointimal thickening.


CONCLUSIONS
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.
Wu
Yih-Jer
YJ
Department of Cardiovascular Medicine and Medical Research, Mackay Memorial Hospital, and Department of Medicine, Mackay Medical College, and Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
Sala-Newby
Graciela B
GB
Shu
Kuo-Tung
KT
Yeh
Hung-I
HI
Nakayama
Keiichi I
KI
Nakayama
Keiko
K
Newby
Andrew C
AC
Bond
Mark
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
C493962:Cdkn1b protein, rat; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27