Abstract
Based on our previous observations that 1-O-acetylbritannilactone (R)-4((3aS,4S,7aR)-4-hydroxy-6-methyl-3-methylene-2-oxo-2,3,3a,4,7,7a-hexahydrobenzofuran-5-yl)pentyl acetate (ABL) suppresses prostaglandin E2 and nitric oxide synthesis in macrophages, the present study was designed to explore the effect of ABL on neointimal hyperplasia after balloon injury and its mechanism of action. In male Sprague-Dawley rats, 26 mg/kg ABL or polyglycol (control) was administered daily from 3 days before injury to 2 weeks after conventional balloon injury. ABL administration led to a significant reduction in neointimal formation (neointima to media ratio, 1.94 ± 0.43 versus 0.84 ± 0.29, P < 0.01) and proliferative activity of vascular smooth muscle cells after balloon injury in rats. Western blot analysis revealed that this is correlated to the inhibition of nuclear factor (NF)-κB activation and to the reduced expression of cyclooxygenase-2. Investigation of potential signaling pathways demonstrated that ABL inhibited NF-κB activation via the blockade of the inhibitor of NF-κB kinase-β activation and the suppression of the degradation of the inhibitors of NF-κB-α. These findings suggest that ABL is a potential inhibitor of neointimal formation because it blocks injury-induced NF-κB activation and may have beneficial effects in reducing the risk of restenosis after angioplasty.
Footnotes
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This study was supported by the National Nature Science Foundation of the People's Republic of China (Grants 30570661 and 30472167) and by the Hebei Province Natural Science Foundation of the People's Republic of China (Grant C2005000722). J.-K.W. was supported by the Major State Basic Research Development Program of the People's Republic of China (Grant 2005CCA03100).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.127407.
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ABBREVIATIONS: NF, nuclear factor; SMC, smooth muscle cell; ABL, 1-O-acetylbritannilactone, (R)-4((3aS,4S,7aR)-4-hydroxy-6-methyl-3-methylene-2-oxo-2,3,3a,4,7,7a-hexahydrobenzofuran-5-yl)pentyl acetate; PGE2, prostaglandin E2; COX, cyclooxygenase; I, intima; M, media; ELISA, enzyme-linked immunosorbent assay; IκB-α, inhibitor(s) of NF-κB-α; IKK, inhibitor of NF-κB kinase; EMSA, electrophoresis mobility shift assay; PCNA, proliferating cell nuclear antigen.
- Received June 18, 2007.
- Accepted October 1, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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