Faculty Collaboration Database

Retinoic acid-induced tissue transglutaminase and apoptosis in vascular smooth muscle cells. Circ Res 2000 Nov 10;87(10):881-7

Date

11/14/2000

Pubmed ID

11073883

DOI

10.1161/01.res.87.10.881

Scopus ID

2-s2.0-0034634295 (requires institutional sign-in at Scopus site)   55 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, suggesting a potential mechanistic link between this retinoid-inducible gene and programmed cell death.

Author List

Ou H, Haendeler J, Aebly MR, Kelly LA, Cholewa BC, Koike G, Kwitek-Black A, Jacob HJ, Berk BC, Miano JM

Author

Anne E. Kwitek PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Blotting, Northern
Blotting, Western
Cadaverine
Cells, Cultured
Chromosome Mapping
Cloning, Molecular
Cystamine
Dose-Response Relationship, Drug
Enzyme Inhibitors
GTP-Binding Proteins
Growth Substances
Male
Molecular Sequence Data
Muscle, Smooth, Vascular
RNA, Messenger
Rats
Rats, Sprague-Dawley
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Transcription, Genetic
Transglutaminases
Tretinoin