Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1891-1895
doi: 10.1161/hq1201.100261
doi: 10.1161/hq1201.100261
© 2001 American Heart Association, Inc.
Brief Reviews |
PPAR
and Atherosclerosis
Effects on Cell Growth and Movement
From the Division of Endocrinology, Diabetes and Hypertension, UCLA, Department of Medicine, Los Angeles, Calif.
Correspondence to Dr. Willa A. Hsueh, 900 Veteran Ave, 24-130, Los Angeles, CA 90097-7073. E-mail whsueh{at}mednet.ucla.edu
Atherosclerosis is a major vascular complication of diabetes and the primary cause of mortality in persons with this disease. Metabolic abnormalities related to the Insulin Resistance Syndrome or Metabolic Syndrome may importantly contribute to the increased risk of atherosclerosis associated with diabetes. Thiazolidinediones (TZDs) are oral insulin sensitizers in broad clinical use that enhance insulin-stimulated glucose uptake into skeletal muscle. TZDs can also improve cardiovascular risk factors and exert direct effects on vascular cells to potentially retard the atherosclerotic process. Direct vascular effects of TZDs likely result from their activity as ligands for the nuclear receptor, PPAR
. All of the major cell types in the vasculature express PPAR, including intimal macrophages and vascular smooth muscle cells (VSMCs) in human atheroma. TZDs block VSMC growth by inducing cell cycle arrest in G1 through an inhibition of retinoblastoma protein phosphorylation. Migration of monocytes and VSMCs is also inhibited by TZDs, possibly through decreased matrix metalloproteinase production. Activation of PPAR by TZDs in macrophages induces ABCA1 transporter expression to promote reverse cholesterol transport. These antiatherogenic activities may also occur in vivo because TZDs have been shown to inhibit lesion formation in several animal models. Thus, TZD activation of PPAR may protect against atherosclerosis both by normalizing proatherogenic metabolic abnormalities of the insulin resistance/diabetes milieu and through an inhibition of vascular cell growth and movement.
Key Words: atherosclerosis • PPAR • cell cycle • thiazolidinedione
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