| Abstract: |
Rapamycin, an immunosuppressant and antiproliferative agent, reduces intima hyperplasia after arterial injury in animal models and in a preliminary study in humans. Rapamycin treatment reportedly increases expression of p27, a cyclin-dependent kinase inhibitor. This mechanism was tested using a p27-deficient (p27 -/-) murine model. Aortic smooth muscle cells from wild-type (WT) and p27 -/- mice were isolated and cultured. Cell proliferation, assessed by cell count and 3H-thymidine incorporation, was inhibited significantly by rapamycin in WT and p27 -/- cells at concentrations of 1 rig/mi, 10 ng/ml, and 100 rig/mi (p < 0.05, versus control). The in vivo effect on intimal hyperplasia was studied in p27 -/- and WT mice after femoral artery transluminal injury. Rapamycin treatment was started 2 days before injury and maintained for 2 weeks (1 rog/kg per 48 hours, ip). No significant differences in intima-to-media ratio were found between WT (1.1 ± 0.1) and p27 -/- mice (1.0 ± 0.1) 4 weeks after injury. Rapamycin significantly (p < 0.05) reduced intima-to-media ratios in both WT (0.7 ± 0.1) and p27 -/- mice (0.5 ± 0.1), compared with untreated mice. p27 deficiency did not alter the arterial wall proliferative response to injury. The inhibitory effect of rapamycin on intimal hyperplasia occurred via a p27-independent mechanism. The in vitro data showed that this effect was mediated through decreased proliferation and enhanced apoptosis. |
| Keywords: |
gene deletion; nonhuman; cell proliferation; mouse; animals; cell cycle proteins; mice; mice, knockout; animal tissue; cell division; apoptosis; enzyme inhibition; animal model; mice, inbred c57bl; hyperplasia; protein p27; cyclin-dependent kinase inhibitor p27; tumor suppressor proteins; cell isolation; cell count; immunosuppressive treatment; rapamycin; sirolimus; immunosuppressive agents; knockout mouse; artery injury; tunica intima; muscle, smooth, vascular; femoral artery; microtubule-associated proteins; aorta; wounds, nonpenetrating; artery intima proliferation; male; female; priority journal; article
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