| ǥ :
|
ȣ - 480342 291 |
| Rosiglitazone Reduces Neointimal Hyperplasia by Inhibition of Matrix Metalloproteinases-9 and ERK/GSK Pathway in Rat Carotid Injury Model |
| 서울대학교병원 임상의학연구소 심혈관연구실 1),서울대학교의과대학 내과학교실 2), 서울대학교병원 심혈관센터 3) |
| 김성환1)2)3), 이춘수1), 김태연1), 윤석원1) ,조현재1)2)3), 양한모1)2)3)김효수1)2)3), 오병희1)2)3), 이명묵1)2)3), 박영배1)2)3). 최윤식1)2)3) |
Introduction: Thiazolidinediones have been shown to have an anti-restenotic effect in experimental models. But its mechanism is still unclear. Smooth muscle cell migration and proliferation are a major contributor to neointimal hyperplasia. Migration is partly mediated by the matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). Also GSK regulates cellular processes including proliferation and migration. We assessed the hypothesis that rosiglitazone reduces neointimal hyperplasia through inhibition of MMP-9 and GSK pathway respectively. Methods: In vitro, we evaluated the effects of rosiglitazone on MMP-9/TIMP-1 and migration of rat VSMC. Also Cell viability and proliferation which mediated by GSK pathway were measured using WST-1 assay and BrdU incorporation. Then in-vivo, we compared the effect of rosiglitazone (3mg/kg) and control in two groups (n=10/group) of rats with denudated carotid artery. Treatment was started 3 days before injury and continued for 2weeks after injury. Results: In-vitro, rosiglitazone suppressed MMP-9 in immunoblot analysis and zymography of rat VSMC and potentiated TIMP-1 conversely, which led to the inhibition of VSMC migration in scratch assay. And rosiglitazone attenuates the activation of phospho-ERK and phospho-GSK in immunoblot, which led to decrease number of viable cells in WST-1 assay and inhibit proliferation in BrdU incorporation. In-vivo, at 3d after balloon injury, rosiglitazone significantly decreased proliferation in PCNA assay. In morphometry at 2wk, rosiglitazone significantly decreased the ratio of Intima to Media (control vs. rosiglitazone 1.14±0.15 vs. 0.53±0.18, p<0.05), also lumen area increased though it is not significant statistically (0.97±0.17 vs. 1.26±0.12, p = 0.11). Conclusions: Rosiglitazone is a potential inhibitor of neointimal formation, through suppression of MMP-9 and potentiation of TIMP-1 reciprocally. Also rosiglitazone attenuates the activation of phospho-ERK and phospho-GSK, which leads to decreased cell viability and proliferation.
|
|
|
|
|
