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Retinoids inhibit proliferation of human coronary smooth muscle cells by modulating cell cycle regulators
1Division of Endocrinology, Diabetes, and Hypertension, School of Medicine, University of California, Los Angeles 90095, USA.
Abstract:
Retinoids inhibit rat vascular smooth muscle cell (VSMC) proliferation in vitro and intimal hyperplasia in vivo. We examined the mechanism of the antiproliferative effect of retinoids on human coronary artery smooth muscle cells (human CASMCs). The RAR ligands all-trans-retinoic acid (atRA) and ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-propenyl]-benzoic acid (TTNPB); a pan-RXR/RAR agonist, 9-cis-retinoic acid (9cRA); and the RXR-selective ligand AGN4204 all inhibited DNA synthesis stimulated with platelet-derived growth factor and insulin (IC(50): TTNPB 63 nmol/L, atRA 120 nmol/L, AGN4204 460 nmol/L, 9cRA 1.5 micromol/L). All retinoids blocked cell cycle progression as determined by flow cytometry and inhibited retinoblastoma protein (Rb) phosphorylation. TTNPB, atRA, and AGN4204 inhibited the 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 retinoids attenuated mitogen-induced downregulation of CDKI p27(Kip1), a major negative regulator of Rb phosphorylation, partly through stabilizing p27(Kip1) turnover. These data demonstrate that retinoids have antiproliferative activity by modulating G(1) --> S cell cycle regulators in human CASMCs through inhibition of Rb phosphorylation and elevation of p27(Kip1) levels.
Insights
Retinoids, including all-trans-retinoic acid (atRA) and TTNPB, inhibit human coronary artery smooth muscle cell (hCASMC) proliferation by blocking cell cycle progression and Rb phosphorylation. They also increase p27(Kip1) levels, a key cell cycle regulator.
Area of Science:
- Cardiovascular Biology
- Molecular Pharmacology
- Cell Cycle Regulation
Background:
- Retinoids are known to inhibit vascular smooth muscle cell (VSMC) proliferation.
- Vascular smooth muscle cell (VSMC) proliferation contributes to intimal hyperplasia.
- Understanding the precise mechanisms of retinoid action on human coronary artery smooth muscle cells (hCASMCs) is crucial.
Purpose of the Study:
- To investigate the antiproliferative mechanisms of various retinoids on human coronary artery smooth muscle cells (hCASMCs).
- To determine how retinoids affect cell cycle progression and key regulatory proteins in hCASMCs.
Main Methods:
- Treatment of hCASMCs with retinoids (atRA, TTNPB, 9cRA, AGN4204) and mitogens (PDGF, insulin).
- Assessment of DNA synthesis, cell cycle progression via flow cytometry, and protein levels (Rb, cyclins, CDKI p27(Kip1)).
Main Results:
- Retinoids (TTNPB, atRA, AGN4204, 9cRA) significantly inhibited DNA synthesis and cell cycle progression in hCASMCs.
- Retinoids blocked retinoblastoma protein (Rb) phosphorylation and attenuated mitogen-induced downregulation of CDKI p27(Kip1).
- Specific retinoids modulated cyclin D1 induction, while all affected p27(Kip1) stability.
Conclusions:
- Retinoids exert antiproliferative effects on hCASMCs by targeting G(1) to S phase transition regulators.
- Inhibition of Rb phosphorylation and elevation of p27(Kip1) are key mechanisms underlying retinoid-mediated antiproliferation in hCASMCs.
- These findings highlight the therapeutic potential of retinoids in preventing vascular smooth muscle cell proliferation.