Regulation of cellular proliferation and intimal formation following balloon injury in atherosclerotic rabbit arteries

Robert D. Simari, Hong San, Mark Rekhter, Takeshi Ohno, David Gordon, Gary J. Nabel, Elizabeth G. Nabel

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Injury to atherosclerotic arteries induces the expression of growth regulatory genes that stimulate cellular proliferation and intimal formation. Intimal expansion has been reduced in vivo in nonatherosclerotic balloon-injured arteries by transfer of genes that inhibit cell proliferation. It is not known, however, whether vascular cell proliferation can be inhibited after injury in more extensively diseased atherosclerotic arteries. Accordingly, the purpose of this study was to investigate whether expression of recombinant genes in atherosclerotic arteries after balloon injury could inhibit intimal cell proliferation. To test this hypothesis, we examined the response to balloon injury in atherosclerotic rabbit arteries after gene transfer of herpesvirus thymidine kinase gene (tk) and administration of ganciclovir. Smooth muscle cells from hyperlipidemic rabbit arteries infected with adenoviral vectors encoding tk were sensitive to ganciclovir, and bystander killing was observed in vitro. In atherosclerotic arteries, a human placental alkaline phosphatase reporter gene was expressed in intimal and medial smooth muscle cells and macrophages, identifying these cells as targets for gene transfer. Expression of tk in balloon-injured hyperlipidemic rabbit arteries followed by ganciclovir treatment resulted in a 64% reduction in intimal cell proliferation 7 d after gene transfer (P = 0.004), and a 35-49% reduction in intimal area 21 d after gene transfer, compared with five different control groups (P < 0.05). Replication of smooth muscle cells and macrophages was inhibited by tk expression and ganciclovir treatment. These findings indicate that transfer of a gene that inhibits cellular proliferation limits the intimal area in balloon-injured atherosclerotic arteries. Molecular approaches to the inhibition of cell proliferation in atherosclerotic arteries constitute a possible treatment for vascular proliferative diseases.

Original languageEnglish (US)
Pages (from-to)225-235
Number of pages11
JournalJournal of Clinical Investigation
Volume98
Issue number1
StatePublished - Jul 1 1996
Externally publishedYes

Fingerprint

Tunica Intima
Arteries
Cell Proliferation
Rabbits
Wounds and Injuries
Ganciclovir
Thymidine Kinase
Genes
Smooth Muscle Myocytes
Macrophages
Gene Expression
Herpesviridae
Regulator Genes
Vascular Diseases
Reporter Genes
Blood Vessels

Keywords

  • adenoviral vectors
  • gene transfer
  • macrophages
  • smooth muscle cells
  • thymidine kinase

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Simari, R. D., San, H., Rekhter, M., Ohno, T., Gordon, D., Nabel, G. J., & Nabel, E. G. (1996). Regulation of cellular proliferation and intimal formation following balloon injury in atherosclerotic rabbit arteries. Journal of Clinical Investigation, 98(1), 225-235.

Regulation of cellular proliferation and intimal formation following balloon injury in atherosclerotic rabbit arteries. / Simari, Robert D.; San, Hong; Rekhter, Mark; Ohno, Takeshi; Gordon, David; Nabel, Gary J.; Nabel, Elizabeth G.

In: Journal of Clinical Investigation, Vol. 98, No. 1, 01.07.1996, p. 225-235.

Research output: Contribution to journalArticle

Simari, RD, San, H, Rekhter, M, Ohno, T, Gordon, D, Nabel, GJ & Nabel, EG 1996, 'Regulation of cellular proliferation and intimal formation following balloon injury in atherosclerotic rabbit arteries', Journal of Clinical Investigation, vol. 98, no. 1, pp. 225-235.
Simari, Robert D. ; San, Hong ; Rekhter, Mark ; Ohno, Takeshi ; Gordon, David ; Nabel, Gary J. ; Nabel, Elizabeth G. / Regulation of cellular proliferation and intimal formation following balloon injury in atherosclerotic rabbit arteries. In: Journal of Clinical Investigation. 1996 ; Vol. 98, No. 1. pp. 225-235.
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