Retinoic Acid–Induced Tissue Transglutaminase and Apoptosis in Vascular Smooth Muscle Cells
作者:
Hesheng Ou,
Judith Haendeler,
Michael Aebly,
Louise Kelly,
Brian Cholewa,
George Koike,
Anne Kwitek-Black,
Howard Jacob,
Bradford Berk,
Joseph Miano,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2000)
卷期:
Volume 87,
issue 10
页码: 881-887
ISSN:0009-7330
年代: 2000
出版商: OVID
关键词: tretinoin;transcription;protein-glutamine &ggr;-glutamyltransferase;chromosome;cDNA
数据来源: OVID
摘要:
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-transretinoic acid (atRA). The induction of tTG was selective for atRA and its stereoisomers 9-cisand 13-cisRA, 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, suggesting a potential mechanistic link between this retinoid-inducible gene and programmed cell death.
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