on April 3, 2008
Published online before print April 3, 2008, doi: 10.1161/ATVBAHA.108.162362
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Submitted on August 31, 2007
Accepted on March 20, 2008
CCN1 Knockdown Suppresses Neointimal Hyperplasia in a Rat Artery Balloon Injury Model
Hironobu Matsumae *;
From the Department of Cardiovascular Medicine (H.M., Y.Y., K.O., K.T., Y.F., Y.N., Y.K., T.K., M.T.), Graduate School of Medicine, Kyoto University, Kyoto, Japan; the Department of Cardiology (K.I.), Kurashiki Central Hospital, Kurashiki, Japan; and the Department of Cardiology (M.N.), Kokura Memorial Hospital, Kokura, Japan.
* To whom correspondence should be addressed. E-mail: hiromatz{at}kuhp.kyoto-u.ac.jp.
Objective—CCN1 (Cyr61) is an extracellular matrix-associated protein involved in cell proliferation and survival. CCN1 is bound to vascular smooth muscle cells (VSMCs) via integrins and is expressed in VSMCs in atherosclerotic lesions, suggesting involvement in the regulation of vascular smooth muscle cell (VSMC) proliferation and atherosclerosis. We hypothesized that knockdown of CCN1 may inhibit VSMC proliferation and suppress neointimal hyperplasia.
Methods and Results—We examined the effect of the knockdown of CCN1 using rat cultured VSMCs and a rat balloon injury model. CCN1 stimulated adhesion and migration of VSMCs in a dose-dependent manner, and this was blocked by an antibody for integrin 
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1. Moreover, knockdown of endogenous CCN1 by lentiviral delivery of siRNA significantly inhibited proliferation of VSMCs and the uptake of 5-bromo-2'-deoxyuridine (BrdU). Replenishment with recombinant CCN1 reversed the effect of siRNA knockdown. Interestingly, knockdown of CCN1 significantly suppressed neointimal hyperplasia in a rat carotid artery balloon injury model at days 14 and 28 after injury. Gene transfer of CCN1 to smooth muscle reversed the effect of CCN1 knockdown on neointimal formation. These results suggest that endogenous CCN1 regulates proliferation of VSMCs and neointimal hyperplasia.
Conclusion—Inhibition of CCN1 may provide a promising strategy for the prevention of restenosis after vascular interventions.