Control of Vascular Cell Proliferation and Migration by PPAR-γ

A new approach to the macrovascular complications of diabetes

  1. Willa A. Hsueh, MD,
  2. Simon Jackson, PHD and
  3. Ronald E. Law, PHD, JD
  1. From the Department of Medicine, the Endocrinology, Diabetes, and Hypertension Division, University of California School of Medicine, Los Angeles, California.
  1. Address correspondence to Willa Hsueh, MD, UCLA, Division of Endocrinology, Diabetes and Hypertension, 240130 Warren Hall, Los Angeles, CA 90095-7073. Address reprint requests to Cadmus Journal Services Reprints, P.O. Box 751903, Charlotte, NC 28275-1903.

Abstract

Compared with nondiabetic subjects, type 2 diabetic individuals are at an increased risk for coronary artery disease and coronary restenosis after angioplasty or stenting. Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. Therefore, pharmaceutical interventions targeting proteins that regulate VSMC growth or movement are a promising new approach to treat diabetes-associated cardiovascular disease. Peroxisome proliferator—activated receptor-γ (PPAR-γ) is a member of the nuclear receptor superfamily that, when activated by thiazolidinedione (TZD) insulin sensitizers, regulates a host of target genes. All of the major cells in the vasculature express PPAR-γ, including endothelial cells, VSMCs, and monocytes/macrophages. PPAR-γ is present in intimal macrophages and VSMCs in early human atheromas. In an animal model of vascular injury, PPAR-γ levels are substantially elevated in the neointima that forms after mechanical injury of the endothelium. Recent experimental studies provide evidence that PPAR-γ may function to protect the vasculature from injury. Cell culture studies have shown that TZD PPAR-γ ligands inhibit both the proliferation and migration of VSMCs. These antiatherogenic activities of PPAR-γ may also occur in vivo, because TZDs inhibit lesion formation in several animal models. PPAR-γ ligands may also protect the vasculature indirectly by normalizing metabolic abnormalities of the diabetic milieu that increase cardiovascular risk. Activation of PPAR-γ, newly defined in vascular cells, may be a useful approach to protect the vasculature in diabetes.

Footnotes

  • W.A.H. and R.E.L. have received honoraria from Warner Lambert, Parke-Davis, and SmithKline Beecham.

  • Abbreviations: CDK, cyclin-dependent kinase; CDKI, CDK inhibitor; ICAM-1, intracellular adhesion molecule-1; IMT, intimal medial wall thickness; LDLR, LDL receptor; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MMP, metalloproteinase; PAI-1, plasminogen activator inhibitor-1; PDGF, platelet-derived growth factor; PI3-K, phosphatidylinositol 3-kinase; PPAR-γ, peroxisome proliferator-activated receptor-γ; Rb, retinoblastoma; TZD, thiazolidinedione; VCAM-1, vascular cell adhesion molecule-1; VSMC, vascular smooth muscle cell.

  • A table elsewhere in this issue shows conventional and Système International (SI) units and conversion

    • Accepted September 29, 2000.
    • Received June 21, 2000.
| Table of Contents