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  • Title: Inhibition of vascular smooth muscle cell proliferation by DNA-RNA chimeric hammerhead ribozyme targeting to rat platelet-derived growth factor A-chain mRNA.
    Author: Hu WY, Fukuda N, Nakayama M, Kishioka H, Kanmatsuse K.
    Journal: J Hypertens; 2001 Feb; 19(2):203-12. PubMed ID: 11212962.
    Abstract:
    BACKGROUND: Spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells (VSMC) show exaggerated growth and increasingly express platelet-derived growth factor (PDGF) A-chain mRNA compared to VSMC from normotensive Wistar-Kyoto (WKY) rats. OBJECTIVE: To investigate the effects of designed DNA-RNA chimeric hammerhead ribozyme to rat PDGF A-chain on exaggerated growth of VSMC from SHR. DESIGN AND METHODS: We designed and synthesized a 38-base DNA-RNA chimeric hammerhead ribozyme with two phosphorothioate linkages at the 3' terminal to cleave rat PDGF A-chain mRNA at the GUC sequence at nucleotide 921. We confirmed the cleavage activity of designed ribozyme by in vitro cleavage reaction and by lipofectin-mediated transfection of ribozyme into VSMC. RESULTS: Doses of 0.1 and 1 micromol/l DNA-RNA chimeric ribozyme dose-dependently inhibited basal DNA synthesis in VSMC from SHR. A dose of 1 micromol/l DNA-RNA chimeric ribozyme time-dependently inhibited basal DNA synthesis in VSMC from SHR. However, the same doses of all-RNA ribozyme had no effects on DNA synthesis in VSMC from SHR. Fluorescein isothiocyanate-labeled DNA-RNA chimeric ribozyme was recognized in cytosol at 30 min, and in nucleus at 60 min after lipofectin transfection. A dose of 1 micromol/l DNA-RNA chimeric ribozyme significantly inhibited expressions of both PDGF A-chain mRNA and PDGF-AA protein in VSMC from SHR, but not from WKY rats. CONCLUSION: These results indicated that the designed DNA-RNA chimeric ribozyme to PDGF A-chain mRNA effectively and specifically inhibited the exaggerated growth of VSMC from SHR at low concentrations, which were mediated by the reduction of PDGF A-chain mRNA and PDGF-AA protein expressions.
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