Retinoic acid-induced tissue transglutaminase and apoptosis in vascular smooth muscle cells

Hesheng Ou, Judith Haendeler, Michael R. Aebly, Louise A. Kelly, Brian C. Cholewa, George Koike, Anne Kwitek-Black, Howard J. Jacob, Bradford C. Berk, Joseph M. Miano

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Retinoids exert antiproliferative and prodifferentiating effects in vascular smooth muscle cells (SMCs) and reduce neointimal mass in balloon-injured blood vessels. The mechanisms through which retinoids carry out these effects are unknown but likely involve retinoid receptor-mediated changes in gene expression. Here we report the cloning, chromosomal mapping, and biological activity of the retinoid-response gene rat tissue transglutaminase (tTG). Northern blotting studies showed that tTG is rapidly and dose-dependently induced in a protein synthesis-independent manner after stimulation with the natural retinoid all-trans retinoic acid (atRA). The induction of tTG was selective for atRA and its stereoisomers 9-cis and 13-cis RA, because little or no elevation in mRNA expression was observed with a panel of growth factors. Western blotting and immunofluorescence confocal microscopy showed an accumulation of cytosolic tTG protein after atRA stimulation. Radiolabeled cross-linking studies revealed a corresponding elevation in in vitro tTG activity. The increase in tTG activity was reduced in the presence of 2 distinct inhibitors of tTG (monodansylcadaverine and cystamine), atRA-induced tTG mRNA and protein expression were followed by a significant elevation in SMC apoptosis. Such retinoid-induced programmed cell death could be partially inhibited with each tTG inhibitor and was completely blocked when both inhibitors were used simultaneously. These results establish a role for atRA in the sequential stimulation of tTG and apoptosis in cultured SMCs. atRA-mediated apoptosis in SMCs seems to require the participation of active tTG, suggestihg a potential mechanistic link between this retinoid-inducible gene and programmed cell death.

Original languageEnglish (US)
Pages (from-to)881-887
Number of pages7
JournalCirculation research
Volume87
Issue number10
DOIs
StatePublished - Nov 10 2000
Externally publishedYes

Keywords

  • CDNA
  • Chromosome
  • Protein-glutamine γ-glutamyltransferase
  • Transcription
  • Tretinoin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Ou, H., Haendeler, J., Aebly, M. R., Kelly, L. A., Cholewa, B. C., Koike, G., Kwitek-Black, A., Jacob, H. J., Berk, B. C., & Miano, J. M. (2000). Retinoic acid-induced tissue transglutaminase and apoptosis in vascular smooth muscle cells. Circulation research, 87(10), 881-887. https://doi.org/10.1161/01.RES.87.10.881