Simvastatin decreases stent-induced in-stent restenosis rate via downregulating the expression of PCNA and upregulating that of p27kip1.
BACKGROUND
The inhibition of the proliferation and migration of vascular smooth muscle cells (VSMC) is one cholesterol-independent effect of statins that could lower the rate of in-stent restenosis (ISR), even if the exact mechanism remains unclear. The aim of this study was to explore the exact inhibitory mechanisms of simvastatin on ISR in vivo.


METHODS
Forty-five rabbits were randomized into 3 feeding groups of equal size (n=15): normal rabbit chow (normal group), a high-cholesterol diet (control group), and a simvastatin-enriched high-cholesterol diet (simvastatin group). Balloon de-endothelialization was first performed in the control and simvastatin groups after 3 days, followed by stent deployment at week 14. All rabbits were killed at week 18, and the histological changes of the ISR segments were observed. The expressions of cyclin-dependent kinase inhibitor p27 (p27kip1), proliferating cell nuclear antigen (PCNA), and α-smooth muscle (α-SM) actin were measured.


RESULTS
In the simvastatin group compared to the control group, the neointimal thickness, neointimal area, and degree of stenosis decreased, while the residual lumen area increased significantly (P<0.05). Moreover, the expression of α-SM actin in the control group decreased by 55.4% compared to the normal group, while it increased by 29.7% with respect to the simvastatin group (P<0.05). Finally, the expression of p27kip1 increased, while that of PCNA decreased significantly in the simvastatin group compared to the control group (P<0.05).


CONCLUSIONS
Simvastatin may inhibit VSMC phenotype modulation and proliferation by downregulating the expression of PCNA and upregulating that of p27kip1.
Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou, P.R. China.
Chuanyu
C
Gao
Wenke
W
Xu
Wentao
W
Xiao
Jie
J
Yu
Muwei
M
Li
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003324:Coronary Artery Disease / Q000378:metabolism; D023903:Coronary Restenosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011817:Rabbits; D011897:Random Allocation; D019821:Simvastatin / Q000494:pharmacology*; D015607:Stents / Q000009:adverse effects*; D015854:Up-Regulation / Q000187:drug effects
D007166:Immunosuppressive Agents; D018809:Proliferating Cell Nuclear Antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019821:Simvastatin