Inhibition of cell cycle progression and migration of vascular smooth muscle cells by prostaglandin D2 synthase: resistance in diabetic Goto-Kakizaki rats.
The regulation of vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis plays a clear role in the atherosclerotic process. Recently, we reported on the inhibition of the exaggerated growth phenotype of VSMCs isolated from hypertensive rats by lipocalin-type prostaglandin D2 synthase (L-PGDS). In the present study, we report the differential effects of L-PGDS on VSMC cell cycle progression, migration, and apoptosis in wild-type VSMCs vs. those from a type 2 diabetic model. In wild-type VSMCs, exogenously added L-PGDS delayed serum-induced cell cycle progression from the G1 to S phase, as determined by gene array analysis and the decreased protein expressions of cyclin-dependent kinase-2, p21(Cip1), and cyclin D1. Cyclin D3 protein expression was unaffected by L-PGDS, although its gene expression was stimulated by L-PGDS in wild-type cells. In addition, platelet-derived growth factor-induced VSMC migration was inhibited by L-PGDS in wild-type cells. Type 2 diabetic VSMCs, however, were resistant to the L-PGDS effects on cell cycle progression and migration. L-PGDS did suppress the hyperproliferation of diabetic cells, albeit through a different mechanism, presumably involving the 2.5-fold increase in apoptosis and the concomitant 10-fold increase of L-PGDS uptake we observed in these cells. We propose that in wild-type VSMCs, L-PGDS retards cell cycle progression and migration, precluding hyperplasia of the tunica media, and that diabetic cells appear resistant to the inhibitory effects of L-PGDS, which consequently may help explain the increased atherosclerosis observed in diabetes.
Ragolia
Louis
L
Vascular Biology Laboratory, Winthrop-University Hospital, Mineola, New York 11501, USA. lragolia@winthrop.org
Palaia
Thomas
T
Koutrouby
Tara B
TB
Maesaka
John K
JK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001161:Arteriosclerosis / Q000503:physiopathology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000187:drug effects* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D019746:Intramolecular Oxidoreductases / Q000494:pharmacology*; D054834:Lipocalins; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D051381:Rats
D018797:Cell Cycle Proteins; D054834:Lipocalins; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase