회원로그인

мȸ ǥ ʷ

ǥ : ͱ ȣ - 470211   41 
Lacidipine reduces neointimal hyperplasia by inhibition of MMP-9 expression in rat carotid injury model
서울대학교병원 심혈관센터, 임상의학연구소 심혈관연구실, 서울대학교 의과대학 내과학교실
김성환, 전수인,양한모,박승정,김효수,손대원,오병희,이명묵,박영배,최윤식
Background Lacidipine is a dihydropyridine calcium channel blocker with excellent safety and tolerability. It has been known to have an anti-oxidant effect and MMP-9 (matrix metalloproteinase) modulation. The response to arterial balloon injury involves MMP-dependent SMC migration and can be attenuated in vivo by the expression of TIMP-1(tissue inhibiter of metalloproteinase) by gene transfer. Based on this mechanism, we examined the effects of lacidipine on reducing neointimal hyperplasia after balloon injury. Method & Result Rats weighing approximately 250mg (9 weeks) were used. We fed rats hypercholesterol fodder all over experiment. They were pretreated with lacidipine 3mg/kg dissolved in 1ml of vehicle daily by gavage for 3 days before balloon injury (n=8). Controls were given corn oil in the same way (n=8). The endothelium of rat carotid artery was denuded with 2 Fr Fogarty catheter by an operator who did not know about pretreatment. Then lacidipine or corn oil administration continued for 2 weeks after balloon injury. 2 weeks later after injury, we harversted all rats, and examine morphometry, measure MMP-9 expression by immunohistochemistry. As supporting this data, we evaluated the effect of lacidipine on MMP-9 expression in human macrophage in vitro. Although lacidipine has a no effect for neointima reduction at low dose(0.3mg/kg), lacidipine high dose(3mg/kg) therapy reduced intima-media ratio by 22% compared with control group at 2 weeks after balloon injury (lacidipine 3mg vs control, neointima : 0.14 ?0.03 vs 0.10 ?0.04, P=0.009, neointima-to-media ratio : 0.96 ?0.09 vs 0.75 ?0.07, P= 0.02). In the IHC for MMP-9, lacipidine-treated group showed the reduced activity of MMP-9 compared with control group. In vitro study, Lacidipine (1?0 mM) significantly reduced, in a dose dependent MMP-9 potential gelatinolytic capacity up to 50% Conclusion Systemic oral lacidipine therapy attenuates neointimal hyperplasia through inhibition of injury-induced MMP-9 activation. Its clinical implication is very bright. lacidipine would be have a broader indication and be a first choice of calcium channel blocker for the patients with coronary artery disease, especially after angioplasty.


[ư]