Deficiency of clusterin inhibits neointimal hyperplasia after vascular injury.
OBJECTIVE
Increased clusterin mRNA and protein levels have been detected in various tissues undergoing stress, and we previously reported that clusterin is markedly induced in media and neointima following vascular injury. The present study therefore investigated the impact of clusterin on neointimal hyperplasia following vascular injury.


RESULTS
As compared with wild-type mice, clusterin knockout mice (clusterin-KO) demonstrated a significant decrease of the intima/media ratio 4 weeks after cuff placement. Immunohistochemical analysis of injured femoral arteries in clusterin-KO demonstrated the accumulation of p53 in nuclei of neointimal vascular smooth muscle cells (VSMCs). Moreover, VSMCs from either clusterin-KO or rat VSMCs treated with clusterin-short-interfering (si) RNA subjected to static stretch exhibited significantly increased p53 and p21, and increased G1 cell cycle arrest as indicated by flow cytometry compared with VSMCs from wild-type mice.


CONCLUSIONS
Reduced clusterin expression reduced the proliferation of VSMCs and induced G1 arrest via p53 and p21. Clusterin therefore represents a promising molecular target to limit restenosis after coronary intervention.
Shirasawa
Takahiro
T
Department of Cardiovascular, Respiratory and Metabolic Medicine, Kagoshima University, Japan.
Miyata
Masaaki
M
Eto
Hideyuki
H
Hamada
Narisato
N
Akasaki
Yuichi
Y
Miyauchi
Takahiro
T
Furusho
Yuko
Y
Orihara
Koji
K
Hamasaki
Shuichi
S
Aronow
Bruce J
BJ
Smith
Jonathan D
JD
Tei
Chuwa
C
D000818:Animals; D051152:Clusterin / Q000172:deficiency*; D023903:Coronary Restenosis / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016193:G1 Phase; D006965:Hyperplasia / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000293:injuries*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D017539:Tunica Intima / Q000293:injuries / Q000473:pathology*
C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D051152:Clusterin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53