1998 Fiscal Year Final Research Report Summary
Development of gene therapy for the vascular proliferative diseases by antisense DNA to PDGF A-chain
| Project/Area Number |
09670763
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Nihon University |
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Principal Investigator |
FUKUDA Noboru Nihon University School of Medicine, Assistant, 医学部, 助手 (40267050)
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| Co-Investigator(Kenkyū-buntansha) |
WATANABE Yoshiyasu Nihon University School of Medicine, Assistant, 医学部, 助手 (10267049)
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| Project Period (FY) |
1997 – 1998
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| Keywords | PDGF A-chain / antisense DNA / gene therapy / vascular smooth muscle cell / spontaneously hypertensive rat / hypertension |
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| Research Abstract |
To evaluate the contribution of PDGF A-chain in the exaggerated growth of cardiovascular organs in hypertension, we examined the effect of antisense oligodeoxynucleotide (ODN) to PDGF A-chain mRNA on the growth of cardiovascular organs in spontaneously hypertensive rats (SHR) in vitro and in vivo. The antisense ODN significantly reduced growth of vascular smooth muscle cells (VSMC) from SHR, but not in cells from normotensive Wistar-Kyoto (WKY) rats. The antisense ODN inhibited the production of the PDGF A-chain protein, but not of the PDGF A-chain mRNA.The injection of 32P-antisense ODN in vivo led to a greater accumulation of radioactivity in the aorta than in other organs. Infusion of antisense ODN for 28 days markedly reduced the exaggerated growth of artery in vivo.
Two isoforms of PDGF A-chain mRNA including or excluding exon 6 are produced. RT-PCR revealed both long- and short-form PDGF A-chain transcripts in VSMC from SHR and WKY rats, with the long-form mRNA more abundant in SH
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R VSMC.Cycle sequencing analysis revealed that rat exon 6 is composed with 70 nucleotides and 8 different bases to human exon 6. The antisense ODN to exon 6 significantly inhibited growth of SHR V.SMC.The antisense ODN to exon 6 abolished expression of the long-form PDGF A-chain mRNA in VSMC, indicating that the long-form of PDGF A-chain also contributes to the exaggerated growth of SHR VSMC.
To evaluate the PDGF A-chain antisense ODN feasibility for treating the cardiovascular organ damages in hypertension, we examined the effects of the PDGF A-chain antisense ODN on cardiovascular organ growth in stroke prone-SHR (SHR-SP) in vivo. A phosphorothioate-linked antisense ODN significantly inhibited growth and PDGF A-chain expression, but did not affect expression of PDGF A-chain mRNA, in aorta and kidney but not in heart. Infusion of the antisense ODN considerably improved the arterial and renal tissue damage in SHR-SP morphologically.
From these findings, it can be confirmed that suppression of PDGF A-chain by the antisense DNA is useful for treating the cardiovascular organ damages in hypertension as a gene therapy, and that high blood pressure is not the primary factor responsible for cardiovascular organ growth in hypertension. Less
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Research Products
(6 results)
