| Objective To investigate the effects of all-trans Retinoic Acid(atRA) on neointima formation and expression of proliferating cell nuclear antigen (PCNA) and Cyclin-dependent kinases (Cdks) after vascular balloon injury, to determine whether atRA can prevent restenosis after percutaneous transluminal coronary angioplasty(PTCA) and the mechanisms.Methods The rats were randomly divided into three groups: non-injuryed group(n=8); control group(n=24); atRA group(n=24), rats were given atRA(30mg/kg/d PO) from 4 days before injury to the day been killed after injury.The aortic tissues were taken at 48h and day 7,14. Morphometric analysis and immunohistochernistry for PCNA,Cdk2 and Cdk4 were performed at different time points.Results (1) In control group(7 and 14days) ,there were distinct intima proliferation and luminal area decreases. (2)Histomorphometry revealed atRA-mediated reductions in neointima area (0.0475 + 0.0091 versus 0.0703 + 0.0135, P<0.05) and intimal/medial area ratio (0.0878 + 0.0206 versus 0.2650 + 0.0565, P<0.05) but no differences between luminal area( 1.8668 + 0.0943 versus 1.7903 +0.1024, P > 0.05) by 7 days, atRA-mediated reductions in neointima area (0.0571 +0.0150 versus 0.1451 + 0.0324, P<0.01) , intimal/medial area ratio (0.1084 + 0.0326 versus 0.2650 + 0.0565, P<0.01) as well as significant increases in luminal area (1.9134 + 0.1106 versus 1.6908 + 0.1129, P<0.01) by 14 days, (3)Immunohistochemical analysis revealed expression of PCNA,Cdk2 and Cdk4 within the media of injured thoracic arteries at 48 hours time point. At 7days time points, expression of these markers declined to basal levels in the media but was detected within the intimal lesion . By 14 days, when a prominent intimal lesion was formed, they were largely confined to the luminal surface. (4) Less CDK2 immunostaining were found in the atRA group than in control group (media 48h 11.3544+1.2197 versus 19.8093 + 1.6687, P<0.01, media 7d 5.7656+1.0459 versus 8.3853 + 1.0581, P<0.01, intima 7d 16.7710 + 1.4221 versus 34.3288 + 2.3890, P<0.01 and intima 14d 8.5273 + 0.9065 versus 20.9890 + 2.4703, P<0.01, respectively). (5) Less CDK4 immunostaining were found in the atRA group than in control group(media48h 10.0056+1.5348 versus 21.1949+1.5646, P<0.01, media 7d 5.0044 + 0.6572 versus 7.6520+1.1550, P<0.01 , intima 7d 12.9718+1.1436 versus 31.0500 + 2.2788, P<0.01 andintima 14d 8.5456 + 0.6010 versus 21.4968 + 2.0673, P<0.01, respectively). (6) Less PCNA immunostaining were found in the atRA group than in control group (media 48h 12.1643 + 1.5722 versus 24.168+1.9890, P<0.01 , media 7d 4.6229 + 0.9471 versus 9.8436+1.8201, P<0.01, intima 7d 16.8393 +1.1083 versus 35.6759 + 3.2795, P<0.01 and intima 14d 8.7584+0.8373 versus 21.9235 + 2.6280, P<0.01, respectively).Conclusion (T) Neointima proliferation and luminal area decreases occurred in balloon-injured aorta. (2) Expression of CDK2, CDK4 and PCNA in VSMC increased after balloon withdraw injury. (3)AtRA inhibited the over-expression of CDK2 and CDK4. (4) AtRA inhibited the over-expression of PCNA. (5) AtRA attenuated neointima formation and luminal stenosis distinctly. (6) AtRA may inhitit the VSMC cell cycle by reducing the over-expression of CDK2, CDK4 and PCNA, and then reduce neointimal mass and prevent restenosis.
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