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Prevention of ischemically induced neointimal hyperplasia using ex vivo antisense oligodeoxynucleotides.

Publication ,  Journal Article
Poston, RS; Tran, KP; Mann, MJ; Hoyt, EG; Dzau, VJ; Robbins, RC
Published in: J Heart Lung Transplant
April 1998

BACKGROUND: Chronic graft vascular disease in cardiac allografts results from coronary artery neointimal formation. Vascular ischemia has been shown to provoke the development of neointimal hyperplasia through endothelial damage. We used a rodent model of neointimal formation to test the in vivo effects of antisense oligodeoxynucleotides (AS ODN) specifically designed to block this process. METHODS: Aortas from ACI rats were mock transfected or transfected with 18 base pair AS ODNs against the 5' start codon region of both CDC2 kinase, and proliferating cell nuclear antigen (PCNA) mRNA. Transfection was accomplished by placing the aorta in ODN solution (transfected group, 40 micromol/L of each sequence) or saline solution alone (mock-transfected group) and exposing to hydrostatic pressure (2 atm) for 24 hours at 4 degrees C. Vessels were then interposition-grafted into the abdominal aorta of untreated isogenic recipients and procured on postoperative days (POD) 1, 6, and 14. RESULTS: Nuclear localization of fluorescein isothiocyanate ODN was observed in 81%+/-3% of medial smooth muscle cells at 24 hours after interposition grafting and reperfusion. Efficacy of AS ODNs at blocking CDC2 kinase and PCNA was verified on POD 6 by enzyme-linked immunosorbent assay. This blockade significantly reduced ischemically induced vascular narrowing on POD 14 as assessed by use of computerized image analysis (3.85%+/-2.45% luminal narrowing for transfected vs 7.11%+/-2.03% for control subjects, p < 0.03). CONCLUSIONS: Our data show the efficacy of AS ODN at blocking rat PCNA and CDC2 kinase up-regulation provoked by ischemia. This ex vivo approach had beneficial effects against vascular narrowing in a rodent model of ischemically induced neointimal hyperplasia, an antigen-independent factor important in the development of subsequent chronic graft vascular disease.

Duke Scholars

Published In

J Heart Lung Transplant

ISSN

1053-2498

Publication Date

April 1998

Volume

17

Issue

4

Start / End Page

349 / 355

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tunica Intima
  • Transplantation, Isogeneic
  • Transfection
  • Surgery
  • Rats, Inbred ACI
  • Rats
  • RNA, Messenger
  • Proliferating Cell Nuclear Antigen
  • Oligonucleotides, Antisense
 

Citation

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Poston, R. S., Tran, K. P., Mann, M. J., Hoyt, E. G., Dzau, V. J., & Robbins, R. C. (1998). Prevention of ischemically induced neointimal hyperplasia using ex vivo antisense oligodeoxynucleotides. J Heart Lung Transplant, 17(4), 349–355.
Poston, R. S., K. P. Tran, M. J. Mann, E. G. Hoyt, V. J. Dzau, and R. C. Robbins. “Prevention of ischemically induced neointimal hyperplasia using ex vivo antisense oligodeoxynucleotides.J Heart Lung Transplant 17, no. 4 (April 1998): 349–55.
Poston RS, Tran KP, Mann MJ, Hoyt EG, Dzau VJ, Robbins RC. Prevention of ischemically induced neointimal hyperplasia using ex vivo antisense oligodeoxynucleotides. J Heart Lung Transplant. 1998 Apr;17(4):349–55.
Poston, R. S., et al. “Prevention of ischemically induced neointimal hyperplasia using ex vivo antisense oligodeoxynucleotides.J Heart Lung Transplant, vol. 17, no. 4, Apr. 1998, pp. 349–55.
Poston RS, Tran KP, Mann MJ, Hoyt EG, Dzau VJ, Robbins RC. Prevention of ischemically induced neointimal hyperplasia using ex vivo antisense oligodeoxynucleotides. J Heart Lung Transplant. 1998 Apr;17(4):349–355.
Journal cover image

Published In

J Heart Lung Transplant

ISSN

1053-2498

Publication Date

April 1998

Volume

17

Issue

4

Start / End Page

349 / 355

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tunica Intima
  • Transplantation, Isogeneic
  • Transfection
  • Surgery
  • Rats, Inbred ACI
  • Rats
  • RNA, Messenger
  • Proliferating Cell Nuclear Antigen
  • Oligonucleotides, Antisense