title: Endothelial nitric oxide synthase: a new paradigm for gene regulation in the injured blood vessel.
abstract: Advances in our understanding of the molecular mechanisms involved in the constitutive and regulated expression of endothelial nitric oxide synthase (eNOS) mRNA expression present a new level of complexity to the study of endothelial gene regulation in health and disease. Recent studies highlight the contribution of both transcription and RNA stability to net steady-state mRNA levels of eNOS in vascular endothelium, introducing a new paradigm to gene regulation in the injured blood vessel. Constitutive eNOS expression is dependent on basal transcription machinery in the core promoter, involving positive and negative protein-protein and protein-DNA interactions. Chromatin-based mechanisms and epigenetic events also regulate expression of eNOS at the transcriptional level in a cell-restricted fashion. Although constitutively active, important physiological and pathophysiologic stimuli alter eNOS gene transcription rates. For instance, eNOS transcription rates increase in response to lysophosphatidylcholine, shear stress, and TGF-beta, among others. Under basal conditions, eNOS mRNA is extremely stable. Surprisingly, posttranscriptional mechanisms have emerged as important regulatory pathways in the observed decreases in eNOS expression in some settings. In models of inflammation, proliferation/injury, oxidized low-density lipoprotein treatment, and hypoxia, eNOS mRNA destabilization plays a significant role in the rapid downregulation of eNOS mRNA levels.
authors.affiliation: Renal Division and Department of Medicine, St. Michael's Hospital and University of Toronto, Ontario, Canada.
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Tai
authors.forename: G Brett
authors.initials: GB
authors.lastname: Robb
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D016207:Cytokines / Q000502:physiology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000293:injuries; D004790:Enzyme Induction / Q000187:drug effects; D018056:Hemorheology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009928:Organ Specificity; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse