Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis

Jacobi, Johannes; Sydow, Karsten; Degenfeld, Georges von; Zhang, Ying; Dayoub, Hayan; Wang, Bingyin; Patterson, Andrew J.; Kimoto, Masumi; Blau, Helen M.; Cooke, John P.

doi:10.1161/01.cir.0000158487.80483.09

Cited by 138 publications

(109 citation statements)

References 47 publications

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“…Furthermore, data by Matsumoto et al (6) are in line with findings in DDAH transgenic mice, which exhibit low ADMA levels as a result of high DDAH I activity (22). These animals are less susceptible to vascular lesions (23), which is in part attributable to enhanced angiogenic potential (24), and they have a higher ability to regenerate endothelium (24). In contrast, knocking out this enzyme compromises ADMA degradation, which eventually results in inhibition of NO synthesis, increased vascular resistance and hypertension (25).…”

Section: The Dawn Of a New Treatment For Ckd?supporting

confidence: 54%

A New Perspective for the Treatment of Renal Diseases?

Kielstein¹,

Zoccali²

2007

Journal of the American Society of Nephrology

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Section: The Dawn Of a New Treatment For Ckd?supporting

confidence: 54%

A New Perspective for the Treatment of Renal Diseases?

Kielstein¹,

Zoccali²

2007

Journal of the American Society of Nephrology

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“…One mechanism occurs through renal excretion of ADMA and the other mechanism is through conversion to citrulline and methyamines by the action of DDAH (42). Indeed, overexpression of human DDAH1 in transgenic mice results in a 2-fold increase in NOS activity and nitric oxide production that is associated with 2-fold reduction in plasma ADMA (44,45).…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

Chouinard

Cox

et al. 2006

Journal of Biological Chemistry

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The farnesoid X receptor (FXR, NR1H4) is a bile acid-responsive nuclear receptor that plays critical roles in the transcriptional regulation genes involved in cholesterol, bile acid, triglyceride, and carbohydrate metabolism. By microarray analysis of hepatic genes from female Zucker diabetic fatty (ZDF) rats treated with the FXR agonist GW4064, we have identified dimethylarginine dimethylaminohydrolase-1 (DDAH1) as an FXR target gene. DDAH1 is a key catabolic enzyme of asymmetric dimethylarginine (ADMA), a major endogenous nitric-oxide synthase inhibitor. Sequence analysis of the DDAH1 gene reveals the presence of an FXR response element (FXRE) located 90 kb downstream of the transcription initiation site and within the first intron. Functional analysis of the putative FXRE demonstrated GW4064 dose-dependent transcriptional activation from the element, and we have demonstrated that the FXRE sequence binds the FXR-RXR heterodimer. In vivo administration of GW4064 to female ZDF rats promoted a dose-dependent and >6-fold increase in hepatic DDAH1 gene expression. The level of serum ADMA was reduced concomitantly. These findings provide a mechanism by which FXR may increase endothelium-derived nitric oxide levels through modulation of serum ADMA levels via direct regulation of hepatic DDAH1 gene expression. Thus, beneficial clinical outcomes of FXR agonist therapy may include prevention of atherosclerosis and improvement of the metabolic syndrome.The global epidemic of obesity has led to an increasing prevalence of metabolic syndrome, a wide spectrum of metabolic risk factors characterized by abdominal obesity, low levels of high density lipoprotein cholesterol, high triglycerides, hypertension, glucose intolerance, and a systemic proinflammatory state. These risk factors are closely associated with incidence of cardiovascular disease, a leading cause of mortality in industrialized nations (1, 2). In the last decade, several ligand-activated nuclear receptors, such as peroxisome proliferator-activated receptors, liver X receptors, and thyroid hormone receptors, have emerged as promising targets for pharmacological intervention in the treatment of metabolic syndrome (3).Nuclear receptors are transcription factors that serve as intracellular sensors for endocrine hormones and lipid metabolites, such as bile acids, fatty acids, oxysterols, and xenobiotics. To control a variety of physiological processes, receptors bind to specific cis-acting DNA elements and regulate the expression of target genes by cofactor recruitment upon activation by ligands (4). Based on their pharmacological and ligand-binding properties, the nuclear receptor superfamily can be divided into three groups (5). The first group consists of classical steroid hormone receptors that are activated by high affinity ligands. The second group comprises low affinity receptors for metabolic intermediates. The third group corresponds to orphan receptors that have no known ligands.The farnesoid X receptor (FXR, 2 NR1H4) belongs to the second group of the nuc...

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“…However, little is known regarding the role of NO in ESC differentiation to ECs. In the adult mammal, we and others have shown that NO is a potent mitogen and survival factor for ECs, as well as an angiogenic agent [15][16][17]. Because of the important role NO plays in maintaining EC growth in adults, we hypothesized that it may also play a critical role in endothelial development.…”

Section: Introductionmentioning

confidence: 98%

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Huang

Fleißner

Sun

et al. 2010

Stem Cells and Development

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Signaling pathways that govern embryonic stem cell (ESCs) differentiation are not well characterized. Nitric oxide (NO) is a potent vasodilator that modulates other signaling pathways in part by activating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Because of its importance in endothelial cell (EC) growth in the adult, we hypothesized that NO may play a critical role in EC development. Accordingly, we assessed the role of NO in ESC differentiation into ECs. Murine ESCs differentiated in the presence of NO synthase (NOS) inhibitor NG-nitroarginine methyl ester ( l -NAME) for up to 11 days were not signifi cantly different from vehicle-treated cells in EC markers. However, by 14 days, l -NAME-treated cells manifested modest reduction in EC markers CD144, FLK1, and endothelial NOS. ESC-derived ECs generated in the presence of l -NAME exhibited reduced tube-like formation in Matrigel. To understand the discrepancy between early and late effects of l -NAME, we assessed the NOS machinery and observed low mRNA expression of NOS and sGC subunits in ESCs, compared to differentiating cells after 14 days. In response to NO donors or activation of NOS or sGC, cellular cGMP levels were undetectable in undifferentiated ESCs, at low levels on day 7, and robustly increased in day 14 cells. Production of cGMP upon NOS activation at day 14 was inhibited by l -NAME, confi rming endogenous NO dependence. Our data suggest that NOS elements are present in ESCs but inactive until later stages of differentiation, during which period NOS inhibition reduces expression of EC markers and impairs angiogenic function.

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Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis

Cited by 138 publications

References 47 publications

A New Perspective for the Treatment of Renal Diseases?

A New Perspective for the Treatment of Renal Diseases?

Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

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