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The molecular mechanism of actinomycin D in preventing neointimal formation in rat carotid arteries after balloon injury

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Journal of Biomedical Science

Summary

The pathological mechanism of restenosis is primarily attributed to excessive proliferation of vascular smooth muscle cells (SMC). Actinomycin D has been regarded as a potential candidate to prevent balloon injury-induced neointimal formation. To explore its molecular mechanism in regulating cell proliferation, we first showed that actinomycin D markedly reduced the SMC proliferation via the inhibition of BrdU incorporation at 80 nM. This was further supported by the G1-phase arrest using a flowcytometric analysis. Actinomycin D was extremely potent with an inhibitory concentration IC50 at 0.4 nM, whereas the lethal dose LD50 was at 260 μM. In an in vivo study, the pluronic gel containing 80 nM and 80 μM actinomycin D was applied topically to surround the rat carotid adventitia; the thickness of neointima was substantially reduced (45 and 55%, respectively). The protein expression levels of proliferating cell nuclear antigen (PCNA), focal adhesion kinase (FAK), and Raf were all suppressed by actinomycin D. Extracellular signal-regulated kinases (Erk) involved in cell-cycle arrest were found to increase by actinomycin D. These observations provide a detailed mechanism of actinomycin D in preventing cell proliferation thus as a potential intervention for restenosis.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, China Medical University, 91 Hsueh-Shieh Road, Taichung, 404, Taiwan

    C. H. Wu

  2. Department of Biological Science and Technology, School of Medicine, China Medical University, 91 Hsueh-Shieh Road, Taichung, 404, Taiwan

    C. H. Wu & W. C. Chang

  3. Department of Sport Medicine, School of Medicine, China Medical University, 91 Hsueh-Shieh Road, Taichung, 404, Taiwan

    W. C. Chang

  4. Department of Medicine, School of Medicine, China Medical University, 91Hsueh-Shieh Road, Taichung, 404, Taiwan

    J. S. Hung

  5. Department of Biological Science and Technology, Chiao Tung University, Hsinchu, Taiwan

    J. S. Pan & Simon J. T. Mao

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Correspondence to C. H. Wu.

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Wu, C.H., Pan, J.S., Chang, W.C. et al. The molecular mechanism of actinomycin D in preventing neointimal formation in rat carotid arteries after balloon injury. J Biomed Sci 12, 503–512 (2005). https://doi.org/10.1007/s11373-005-6900-5

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  • DOI: https://doi.org/10.1007/s11373-005-6900-5

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