Prostaglandin D2 synthase inhibits the exaggerated growth phenotype of spontaneously hypertensive rat vascular smooth muscle cells.
Lipocalin-type prostaglandin D2 synthase (L-PGDS) has recently been linked to a variety of pathophysiological cardiovascular conditions including hypertension and diabetes. In this study, we report on the 50% increase in L-PGDS protein expression observed in vascular smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR). L-PGDS expression also increased 50% upon the differentiation of normotensive control cells (WKY, from Wistar-Kyoto rats). In addition, we demonstrate differential effects of L-PGDS treatment on cell proliferation and apoptosis in VSMCs isolated from SHR versus WKY controls. L-PGDS (50 microg/ml) was able to significantly inhibit VSMC proliferation and DNA synthesis and induce the apoptotic genes bax, bcl-x, and ei24 in SHR but had no effect on WKY cells. Hyperglycemic conditions also had opposite effects, in which increased glucose concentrations (20 mm) resulted in decreased L-PGDS expression in control cells but actually stimulated L-PGDS expression in SHR. Furthermore, we examined the effect of L-PGDS incubation on insulin-stimulated Akt, glycogen synthase kinase-3beta (GSK-3beta), and ERK phosphorylation. Unexpectedly, we found that when WKY cells were pretreated with L-PGDS, insulin could actually induce apoptosis and failed to stimulate Akt/GSK-3beta phosphorylation. Insulin-stimulated ERK phosphorylation was unaffected by L-PGDS pretreatment in both cell lines. We propose that L-PGDS is involved in the balance of VSMC proliferation and apoptosis and in the increased expression observed in the hypertensive state is an attempt to maintain a proper equilibrium between the two processes via the induction of apoptosis and inhibition of cell proliferation.
Ragolia
Louis
L
Cellular Biology Laboratory, Winthrop-University Hospital, Suite 505-B, 222 Station Plaza North, Mineola, NY 11501, USA. lragolia@winthrop.org
Palaia
Thomas
T
Paric
Enesa
E
Maesaka
John K
JK
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D002455:Cell Division; D004247:DNA / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006943:Hyperglycemia; D007328:Insulin / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism / Q000502:physiology*; D054834:Lipocalins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D011921:Rats, Inbred WKY; D013997:Time Factors
D007328:Insulin; D054834:Lipocalins; D004247:DNA; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D005947:Glucose