Change Of MMP3 In Aorta And The Effect Of Rapamycin Post Balloon Injury In Rat

Background and objective: Although percutaneous transluminal angioplasty and stent implantation are highly procedures to reduce the severity of stenotic artery disease, their long-term success are significantly limited by high rate of restenosis. Several mechanisms have been implicated in the development of restenosis post-injury, including vascular smooth muscle cell(VSMC) activation, migration and proliferation. Extracellular matrix and basement membranes degradation are premising Condition for VSMC migration. Matrix metalloproteinase3 (MMP3) play an important role in the degradation of extracellular matrix. In the present study, we investigated the change of MMP3 in a rat model of restenosis post angioplasty and whether rapamycin administration could reduce neointimal thickening and the mechanism by which rapamycin inhibits VSMCs in vivo.Methods: One hundred and fifty healthy adult male rat were randomized divided into four groups: (1) Sham operation group(n=20). (2) Balloon group (n=40) :received balloon injury only.(3) Cellulose group(n=40) :received the vehicle solution. (4) Rapamycin group(n=40):intramusclar administration of rapamycin (suspended in solution containing 0.2% sodium carboxymethyl cellulose) started 3 days before injury at a dose of 0. 5 mg/kg and continued for 14 days at a dose of 0. 25 mg/kg. Animals were harvested at 3 days,7 days, 14 days, 21 days and 28 days after injury. Abdominal aortas were analyzed for intimal area, mean intimal thickness and intimal/media area ratio. Intimal nuclear cells were counted at 3 days after injury. MMP3 and PCNA and a -Actin within the vessel wall were determined by immmunohischemistry stain. VSMC phenotype was observed by electron microscope. Blood lipid, renal function, white blood cells and body weight were determined. Results: (1) Neointimal area and intimal/media area ratio 14 days after injury showed a 36.4% and 28.9% reduced in the animals receiving rapamycin compared with those receiving cellulose respectively(0. 14 ± 0. 03 mm2 vs 0.23 ± 0. 06mm2 and 17. 70 ± 3. 37% vs 28. 86 ± 10. 25%, respectively, P<0. 01). (2) Nuclear cell counts were lower in intima of rapamycin-treated arteries than in cellulose arteries (8. 88 ± 3. 04 vs 12. 87 ± 3. 44 at 3 days, p<0. 05). (3)MMP3 in vessel wall increased at 3 daysand reached a peak at 14 days after injury. The expression of MMP3 was lower in rapamycin group. (4)MMP3 related to intimal area and mean intimal thickness (r=0.821 and 0.771, respectively). (5) There were a great number of mitochondrion and little myofilament in VSMC 7 days after injury. Rapamycin administration decreased organelles and increased myof ilament. No VSMC of media passed through micro-window in internal elastic lamina into intima in rapamycin group. (6)Blood cholesterol but not renal fuction and white blood cell was higher in rapamycin group. Interstitial pneumonia occurred in the animals receiving high- dose rapamycin. Conclusions:(1) The expression of MMP3 in aorta wall after injury is a developing procedure. Our study first demonstrates rapamycin can result in MMP3 decrease. (2)Rapamycin can reduce the degree of neointimal hyperplasia via inhibiting VSMC migration in vivo. (3)The phenotype of VSMC can be changed by rapamycin. (4)Low-dose rapamycin has little effect on Hematopoietic system and renal fuction. High-dose rapamycin can cause interstitial pneumonia.