Troglitazone up-regulates vascular endothelial argininosuccinate synthase.
Vascular endothelial nitric oxide (NO) production via the citrulline-NO cycle not only involves the regulation of endothelial nitric oxide synthase (eNOS), but also regulation of caveolar-localized endothelial argininosuccinate synthase (AS), which catalyzes the rate-limiting step of the cycle. In the present study, we demonstrated that exposure of endothelial cells to troglitazone coordinately induced AS expression and NO production. Western blot analysis demonstrated an increase in AS protein expression. This increased expression was due to transcriptional upregulation of AS mRNA, as determined by quantitative real time RT-PCR and inhibition by 1-d-ribofuranosylbenzimidazole (DRB), a transcriptional inhibitor. Reporter gene assays and EMSA analyses identified a distal PPARgamma response element (PPRE) (-2471 to -2458) that mediated the troglitazone increase in AS expression. Overall, this study defines a novel molecular mechanism through which a thiazolidinedione (TZD) like troglitazone supports endothelial function via the transcriptional up-regulation of AS expression.
Goodwin
Bonnie L
BL
Department of Molecular Medicine, College of Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC Box 7, Tampa, FL 33612-4799, USA.
Corbin
Karen D
KD
Pendleton
Laura C
LC
Levy
Monique M
MM
Solomonson
Larry P
LP
Eichler
Duane C
DC
D000818:Animals; D001124:Argininosuccinate Synthase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008024:Ligands; D009569:Nitric Oxide / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D000077288:Troglitazone; D015854:Up-Regulation
D002839:Chromans; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D009569:Nitric Oxide; D001124:Argininosuccinate Synthase; D000077288:Troglitazone