TZDs inhibit vascular smooth muscle cell growth independently of the cyclin kinase inhibitors p21 and p27

Divisions of 1 Endocrinology and 2 Nephrology, Department of Internal Medicine, and 3 Cell and Developmental Biology Graduate Group, University of California, Davis 95616; and 4 Department of Veterans Affairs Northern California Health Care System, Mather, California 95655 The thiazolidenediones (TZDs) are commonly used to treat hyperglycemia in type 2 diabetes. Diabetes is associated with macrovascular disease, leading to accelerated atherosclerosis caused by aberrant vascular smooth muscle (VSM) cell proliferation. Although VSM cell proliferation is inhibited by the TZDs, the mechanism of this effect has not been established. Because of reports that the cyclin kinase inhibitors (CKIs) p21 Waf1/Cip1 and p27 Kip1 can exhibit both growth-inhibitory and growth-permissive effects in VSM cells, we asked whether alterations in these cell cycle regulatory proteins are the mechanism by which the TZDs inhibit VSM cell growth. We show that platelet-derived growth factor-BB increases p21 and p27 and that this increase is attenuated by TZDs. Surprisingly, when VSM cells were transfected with antisense oligodeoxynucleotides to p21 and p27, inhibition of DNA synthesis by TZDs occurred to the same degree as in control cells. Furthermore, the TZDs have inhibitory effects on cyclin D1 and cyclin E levels, suggesting another mechanism by which these drugs decrease VSM cell growth. These data suggest that the TZD-mediated reduction in CKI levels is not the sole mechanism for their antiproliferative effects. The observed decrease in levels of the G1 cyclins by the TZDs suggests a possible mechanism of VSM cell growth inhibition. peroxisome proliferator-activated receptor- ; cell cycle; proliferation; atherosclerosis; diabetes