Retinoids inhibit proliferation of human coronary smooth muscle cells by modulating cell cycle regulators

Retinoids inhibit rat vascular smooth muscle cell (VSMC) proliferation in v itro and intimal hyperplasia in vivo. We examined the mechanism of the anti proliferative effect of retinoids on human coronary artery smooth muscle ce lls (human CASMCs). The RAR ligands all-trans-retinoic acid (atRA) and ethy l-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl]- benzoic acid (TTNPB); a pan-RXR/RAR agonist, 9-cis-retinoic acid (9cRA); an d the RXR-selective ligand AGN4204 all inhibited DNA synthesis stimulated w ith platelet-derived growth factor and insulin (IC50:TTNPB 63 nmol/L, atRA 120 nmol/L. AGN4204 460 nmol/L, 9cRA 1.5 mu mol/L). All retinoids blocked c ell cycle progression as determined by flow cytometry and inhibited retinob lastoma protein (Rb) phosphorylation, TTNPB, atRA, and AGN4204 inhibited th e mitogenic induction of cyclin D1, whereas 9cRA had no effect. None of the retinoids affected the expression of CDK 2, 4, or 6 or cyclin E. All retin oids attenuated mitogen-induced downregulation of CDKI p27(Kip1), a major n egative regulator of Rb phosphorylation, partly through stabilizing p27(Kip 1) turnover. These data demonstrate that retinoids have antiproliferative a ctivity by modulating G(1) --> S cell cycle regulators in human CASMCs thro ugh inhibition of Rb phosphorylation and elevation of p27(Kip1) levels.