TZDs inhibit vascular smooth muscle cell growth independently of the cyclin kinase inhibitors p21 and p27.
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.
Hupfeld
C J
CJ
Division of Endocrinology, Department of Internal Medicine, University of California, Davis, California 95616, USA.
Weiss
R H
RH
D000818:Animals; D000077214:Becaplermin; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000077154:Rosiglitazone; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; C039671:ciglitazone