title: Insulin transcriptionally regulates argininosuccinate synthase to maintain vascular endothelial function.
abstract: Diminished vascular endothelial cell nitric oxide (NO) production is a major factor in the complex pathogenesis of diabetes mellitus. In this report, we demonstrate that insulin not only maintains endothelial NO production through regulation of endothelial nitric oxide synthase (eNOS), but also via the regulation of argininosuccinate synthase (AS), which is the rate-limiting step of the citrulline-NO cycle. Using serum starved, cultured vascular endothelial cells, we show that insulin up-regulates AS and eNOS transcription to support NO production. Moreover, we show that insulin enhances NO production in response to physiological cues such as bradykinin. To translate these results to an in vivo model, we show that AS transcription is diminished in coronary endothelial cells isolated from rats with streptozotocin (STZ)-induced diabetes. Importantly, we demonstrate restoration of AS and eNOS transcription by insulin treatment in STZ-diabetic rats, and show that this restoration was accompanied by improved endothelial function as measured by endothelium-dependent vasorelaxation. Overall, this report demonstrates, both in cell culture and whole animal studies, that insulin maintains vascular function, in part, through the maintenance of AS transcription, thus ensuring an adequate supply of arginine to maintain vascular endothelial response to physiological cues.
authors.affiliation: Department of Molecular Medicine, University of South Florida, Morsani College of Medicine, Tampa, FL, USA.
authors.forename: Ricci J
authors.initials: RJ
authors.lastname: Haines
authors.forename: Karen D
authors.initials: KD
authors.lastname: Corbin
authors.forename: Laura C
authors.initials: LC
authors.lastname: Pendleton
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Meininger
authors.forename: Duane C
authors.initials: DC
authors.lastname: Eichler
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001124:Argininosuccinate Synthase / Q000235:genetics*; D002417:Cattle; D002460:Cell Line; D003331:Coronary Vessels / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D007328:Insulin / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*; D014664:Vasodilation
chemical_list: D007328:Insulin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D001124:Argininosuccinate Synthase; D000109:Acetylcholine