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Mechanisms behind the synergistic effect of sirolimus and imatinib in preventing restenosis after intimal injury.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Tigerstedt, Nina-Maria Aavik, Einari Waqas, Muhammad Khurram Hayry, Pekka J. Savolainen-Peltonen, Hanna M. |
| Copyright Year | 2009 |
| Abstract | BACKGROUND We have shown that the combination of sirolimus and imatinib synergistically inhibits denudation-induced neointimal hyperplasia in rats. We have now dissected the mechanisms behind this synergy and evaluated its long-term efficacy. METHODS After aortic denudation injury, rats received established submaximal doses of sirolimus (1.0 mg/kg/day), imatinib (10.0 mg/kg/day), the combination of these, or vehicle per os from 3 days before the operation until 14 days after injury. Vessel histology and complete blood counts were monitored until 90 days after injury. Neointimal cell outgrowth, migration and proliferation were evaluated in ex vivo vessel cultures. Quantitative real-time polymerase chain reaction and immunohistochemistry were used for gene and protein expression analysis. RESULTS The combination therapy caused a synergistic decrease in the number of neointimal nuclei and area throughout the observation period. It also prevented postinjury thrombocytosis and leukocytosis, and almost abolished neointimal cell outgrowth and migration. Furthermore, the combination therapy resulted in upregulation of smooth muscle cell (SMC) markers SM22alpha and cysteine and glycine-rich protein 2, and of the anti-apoptotic BCL2 mRNA. CONCLUSIONS Combination therapy confers superior long-term vasculoprotection, possibly by inhibition of postoperative thrombocytosis and leukocytosis, inhibition of neointimal cell migration to the injury site and maintenance of cell integrity by inhibition of apoptosis and SMC dedifferentiation. |
| Starting Page | 894 |
| Ending Page | 910 |
| Page Count | 17 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.karger.com/Article/Pdf/167272 |
| PubMed reference number | 18984963v1 |
| Alternate Webpage(s) | https://doi.org/10.1159/000167272 |
| DOI | 10.1159/000167272 |
| Journal | Journal of vascular research |
| Volume Number | 46 |
| Issue Number | 3 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Blood Vessel Tissue Complete Blood Count Cumulative Trauma Disorders Endometrial Hyperplasia Glycine Leukocytosis Muscle Cells Myocytes, Smooth Muscle Polymerase Chain Reaction Sirolimus Smooth muscle (tissue) Thrombocytosis imatinib restenosis |
| Content Type | Text |
| Resource Type | Article |
