The Effect Of Simvastatin On Expression Of P～(27kip1) After Stenting In Abdominal Aorta Of Rabbits

Background and Objective: Percutaneous transluminal coronary angioplasty( PTCA)is an important event in the treatment of coronary heart disease. However, restenosis develops in 30%~50% patients within 6 months after PTCA. Stent implantation could reduce restenosis rates, but the in-stent restenosis(ISR) rates remain at 20%~30% after the stent implantation, which is the main limitation for the clinical application of percutaneous coronary intervention( PCI) .The primary pathological characteristic of ISR is the proliferation of vascular smooth muscle cells, which mainly results in the thicken neointima, and the elastic recovery and remolding are not obvious. Therefore, inhibiting VSMC proliferation was important in ISR treatment. Recently, many studies aimed at the mechanism and treatments of ISR in the field. Many clinical trials have showed that statins reduce the incidence of acute coronary events and the mortality of coronary heart disease, but the mechanism was not clear. Recent evidence indicated that some of the cholesterol-independent effect of statins involved in inhibiting the VSMC proliferation by up-regulating the expression of P27kipl. In order to explore the mechanism and the effect of simvastatin (statins) on VSMC proliferation, we utilized rabbit abdominal aorta stenosis model to observe the incidence of abdominal aorta stenosis after ballonde-endotheliazation of abdominal aorta plus 1.5% cholesterol diet for 9 weeks and evaluate the effect of simvastatin on the histomorphological changes of abdominal aorta and the expression of VSMC proliferation related protein P27kipl and proliferating cell nuclear antigen (PCNA).Methods: Forty-five male New Zealand white rabbits were allocated into three groups: normal group (n=15) was on normal diet; control group (n=15) was on 1.5% high cholesterol diet and underwent ballon injury of abdominal aorta from femoral approach and a stent was implanted at stenosis segment when more than 50% stenosis had formed; treatment group (n=15) was given simvastatin 5mg/d after stenting. Rabbits were killed on the 30th day after stenting and stented abdominal aorta was harvested. The target arteries were cut into 2 parts, one part was embeded in paraffin for immunohistological examination, and the other part was embeded in plastic for observing the histological changes of vessels. The expression of P27kipl and PCNA in each group was detected. Results: (1) during the 10th week, atherosclerosis and stenosis of abdominal aorta were observed by ultrasonic Doppler in 30 animals and the degree of stenosis was over 50%. The results of treatment group and control group were as follows, the degree of stenosis was(56.89±1.05)%vs(58.15±1.03)%,P>0.05, the reference lumen diameter was (2.940±0.032) mm vs (2.940±0.031) mm, P>0.05, and the minimum lumen diameter was (1.267±0.032) mm vs (1.227±0.023) mm, P>0.05; atherosclerosis and stenosis of abdominal aorta were observed by angiography in 30 animals. The results of treatment group and control group were as follows: the degree of stenosis was (57.74±1.089)% vs (58.52± 0.948)%, P>0.05, the reference lumen diameter was (2.945±0.031)mm vs (2.948±0.028) mm, P>0.05, and the minimum lumen diameter was (1.244±0.034) mm VS (1.221±0.022) mm, P>0.05; the results between the 2 groups had no significant difference P>0.05, either. (2) The histomorphologic results showed that compared with normal group, in experimental group and control group the abdominal aortic wall developed varied proliferation, which mainly manifested as the neointima mainly composing of smooth muscle cells, foam cell and collagen fiber, however, no obvious changes were found in media and adventitia. The results of treatment group and control group were as follows: the thinkness of neointima of vessel wall was (0.107±0.072)mm vs (0.133±0.047) mm, P<0.01; the neointimial area was (0.975±0.084) mm2 vs(1.350±0.043) mm2, P<0.01; the degree of stenosis was (20.46±2.325)% vs (31.02±1.904)%, P<0.05; and the area of residual lumen of blood vessel was (4.615±0.268) mm2vs (3.775±0.227) mm2, P<0.0\. (3) Immunohistochemical results: when compared with control group the expression of p27^1 in the neointima was increased (IS:7.149±0.305 vs 2.997±0.310, P<0.00\); and the expression of PCNA was decreased(IS: 3.003±0.192 vs 5.268±0.475, PO.001).Conclusion^ 1) The atherosclerosis and stenosis model with rabbits has been successfully established by ballon de-endotheliazation plus cholesterol diet for 9 weeks with rabbits;(2) The results of ultrasonic Doppler are accordant with angiography, besides, it is convenient, liable, and cheap for evaluating the stenosis degree of abdominal aorta. (3) It is showed that: a) Stent implantation could induce the narrowness of the lumen of blood vessel, hyperplastic neointima and higher expression of PCNA in the neointima. b) Simvastatin could decrease the thickness of hyperplastic neointima and the degree of stenosis in the stented aorta, meanwhile, the expression of p27kipl protein increased and that of PCNA decreased in the neointima VSMC cell nuclear. It is supposed that simvastatin may inhibit the proliferation of VSMC and the neointima hyperplasia through up-regulating the expression of P27kipl.