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(Circulation Research. 2000;87:881.)
© 2000 American Heart Association, Inc.

Molecular Medicine

Retinoic Acid–Induced Tissue Transglutaminase and Apoptosis in Vascular Smooth Muscle Cells

Hesheng Ou¹, Judith Haendeler¹, Michael R. Aebly, Louise A. Kelly, Brian C. Cholewa, George Koike, Anne Kwitek-Black, Howard J. Jacob, Bradford C. Berk, Joseph M. Miano

From the Center for Cardiovascular Research (H.O., J.H., B.C.B., J.M.M.), University of Rochester Medical Center, Rochester, NY, and Cardiovascular Research Center (M.R.A., L.A.K., B.C.C., G.K., A.K.-B., H.J.J.), Medical College of Wisconsin, Milwaukee, Wis.

Correspondence to Joseph M. Miano, PhD, Center for Cardiovascular Research, University of Rochester Medical Center, 601 Elmwood Ave, Box 679, Rochester, NY 14642. E-mail Joseph_Miano{at}urmc.rochester.edu

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.

Key Words: tretinoin • transcription • protein-glutamine -glutamyltransferase • chromosome • cDNA

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