Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and -2. American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] Journal article | | Title | Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and -2. | | Author(s) | Ivashchenko CY, Bradley BT, Ao Z, Leiper J, Vallance P, Johns DG | | Institution | GlaxoSmithKline, Metabolic Pathways Center for Excellence in Drug Discovery, King of Prussia, PA 19406, USA. christine.x.ivashchenko@gsk.com | | Source | Am J Physiol Heart Circ Physiol 2010 Jan; 298(1):H251-8. | | MeSH | Amidohydrolases
Arginine
Blotting, Western
Cells, Cultured
Chromatin
Chromatography, High Pressure Liquid
DNA Primers
Endothelial Cells
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Immunoprecipitation
Lentivirus
Nitrites
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Simvastatin
Sterol Regulatory Element Binding Protein 1
Sterol Regulatory Element Binding Protein 2
Transfection
| | Abstract | Asymmetric dimethylarginine (ADMA) has been implicated in the progression of cardiovascular disease as an endogenous inhibitor of nitric oxide synthase. The regulation of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme responsible for metabolizing ADMA, is poorly understood. The transcription factor sterol response element binding protein (SREBP) is activated by statins via a reduction of membrane cholesterol content. Because the promoters of both DDAH1 and DDAH2 isoforms contain sterol response elements, we tested the hypothesis that simvastatin regulates DDAH1 and DDAH2 transcription via SREBP. In cultured endothelial cells, simvastatin increased DDAH1 mRNA expression compared with vehicle. In an ADMA loading experiment, simvastatin treatment resulted in a decrease in ADMA content, an indication of increased DDAH activity. The knockdown of SREBP1c protein led to an increase in DDAH1 mRNA expression and activity, whereas the knockdown of SREBP2 led to a decrease in DDAH1 mRNA expression. The role of SREBP2 in the activation of the DDAH1 was supported by chromatin immunoprecipitation studies demonstrating increased binding of SREBP2 to the DDAH1 promoter upon simvastatin stimulation. These data indicate that SREBP1c might act as a repressor and SREBP2 as an activator of DDAH transcription and activity. This study describes a novel mechanism of reciprocal regulation by the SREBP family members of the DDAH-ADMA system, which represents a potential link between cellular cholesterol content and endothelial dysfunction observed in cardiovascular disease. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19915177 |
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