Isoform-Specific Regulation by
 N
 G
 ,
 N
 G
 -Dimethylarginine Dimethylaminohydrolase of Rat Serum Asymmetric Dimethylarginine and Vascular Endothelium-Derived Relaxing Factor/NO

Wang, Dan; Gill, Pritmohinder; Chabrashvili, Tinatin; Onozato, Maristela L.; Raggio, Julie; Mendonca, Margarida; Dennehy, Kathryn; Li, Min; Modlinger, Paul; Leiper, James; Vallance, Patrick; Adler, Oscar; Leone, Anna; Tojo, Akihiro; Welch, William J.; Wilcox, Christopher S.

doi:10.1161/circresaha.107.158915

Cited by 131 publications

(148 citation statements)

References 27 publications

Supporting

Mentioning

135

Contrasting

Unclassified

Order By: Relevance

“…Similar to our study, these authors noted less vascular oxidative stress in TG versus WT mice following ANG II infusion (13). The effect of a DDAH2 transgene on vascular hypertrophy in the study by Hasegawa et al (13) may be explained by the recent observation that the DDAH2 isoen- zyme plays a greater role for ADMA metabolism in vascular tissue, whereas DDAH1 has a more pronounced effect on serum ADMA levels (39). This may explain the more pronounced effect of DDAH1 (in our study) versus DDAH2 (13) overexpression on systemic ADMA levels compared with WT littermates (37% vs. 26% decrease).…”

Section: Discussionsupporting

confidence: 89%

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

RH, Hilgers KF. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 294: H1058-H1066, 2008. First published December 21, 2007 doi:10.1152/ajpheart.01103.2007.-The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n ϭ 28) were treated with 1.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, 3.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage. dimethylarginine dimethylaminohydrolase; hypertension; transgenic ASYMMETRIC DIMETHYLARGININE (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a potential risk factor and prognostic biomarker in cardiovascular disease (38). Thus far, elevated ADMA levels have been associated with all established cardiovascular risk factors (38). Furthermore, recent data from genetic mouse models indicate a causal role for ADMA in the pathophysiology of vascular disease (7,19). ADMA derives from the posttranslational methylation of L-arginine residues within proteins catalyzed by enzymes called protein arginine methyltransferases (PRMTs). Upon proteolysis, methylarginines are released into the circulation. Although ϳ15% of ADMA are excreted via the urine, the major elimination occurs through enzymatic degradation (ϳ85%) (1). The enzyme dimethylarginine dimethylaminohydrolase (DDAH), of which two isoforms with distinct tissue distribution have been described, catalyzes the hydrolysis of ADMA to L-citrulline and dimethylamine (38).Thus far, clinical studies have mostly addressed the prognostic value of ADMA in cardiovascular or kidney disease as well as the impact of pharmacological interventions aimed at lowering ADMA levels ...

show abstract

Section: Discussionsupporting

confidence: 89%

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…9,22 Using gene silencing techniques, disruption of DDAH1 gene activity induced a 50% increase in ADMA levels, while similar silencing of DDAH2 did not have any effects. 23 These data were supported by another laboratory. 9 Plasma and tissue ADMA and l-NMMA levels in DDAH1 knock-out mice were several folds higher than in wild-type mice.…”

Section: Genetic Variation In the Ddah Genes And Adma Levelsmentioning

confidence: 55%

Genetic variation in the dimethylarginine dimethylaminohydrolase 1 gene (DDAH1) is related to asymmetric dimethylarginine (ADMA) levels, but not to endothelium-dependent vasodilation

et al. 2013

View full text Add to dashboard Cite

Objectives: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. The breakdown of ADMA is mainly governed by the activity of dimethylarginine dimethylaminohydrolases (DDAHs). We investigated if genetic variation in the DDAH1 and DDAH2 genes were related to ADMA and l-arginine levels, as well as measures of endothelium-dependent vasodilation. Methods: In 1016 70-year-old participants of the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (50% women), we measured endothelium-dependent vasodilation (EDV) using the invasive forearm technique with acetylcholine given in the brachial artery and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma l-arginine and ADMA levels were measured by high-performance liquid chromatography and 55 single nucleotide polymorphisms (SNPs) in the DDAH1 and DDAH2 genes were genotyped. Results: Several of the genotypes in the DDAH1 gene were highly significantly related to ADMA levels (p = 10 −7 at best), but not to the l-arginine levels. No relationships between the genotypes in the DDAH2 gene and ADMA or l-arginine levels were found. None of the DDAH1 genotypes being closely related to ADMA levels were significantly related to EDV or FMD. Neither were any of the DDAH2 genotypes closely related to any of the measurements of vasoreactivity. Conclusion: A close relationship was seen between SNPs in the DDAH1, but not DDAH2, gene and ADMA levels. However, variation in those genes was not related to measures of EDV in this elderly population.

show abstract

“…Conversely, in vivo DDAH-2 gene silencing had no effect on plasma ADMA but reduced endothelium-dependent relaxation by 40% (11). These latter findings are particularly intriguing and demonstrate that elevated plasma ADMA is not associated with impaired endothelium-dependent relaxation, whereas loss of DDAH-2 activity is associated with impaired endothelium-dependent relaxation, despite the fact the plasma ADMA levels are not increased (11). These findings are further supported by a recent study demonstrating that down-regulation of DDAH-2 in response to hyperhomocysteinemia was not associated with increased plasma ADMA (25).…”

mentioning

confidence: 91%

“…Other laboratories have demonstrated that DDAH overexpression inhibits ADMA-mediated endothelial function in cerebral arteries and can enhance insulin sensitivity through modulation of nitric oxide (23,24). Using in vivo siRNA techniques, Wang et al (11) demonstrated that DDAH-1 gene silencing increased plasma levels of ADMA by 50%, but this increase had no effect on endothelium-dependent relaxation. Conversely, in vivo DDAH-2 gene silencing had no effect on plasma ADMA but reduced endothelium-dependent relaxation by 40% (11).…”

mentioning

confidence: 99%

“…Using in vivo siRNA techniques, Wang et al (11) demonstrated that DDAH-1 gene silencing increased plasma levels of ADMA by 50%, but this increase had no effect on endothelium-dependent relaxation. Conversely, in vivo DDAH-2 gene silencing had no effect on plasma ADMA but reduced endothelium-dependent relaxation by 40% (11). These latter findings are particularly intriguing and demonstrate that elevated plasma ADMA is not associated with impaired endothelium-dependent relaxation, whereas loss of DDAH-2 activity is associated with impaired endothelium-dependent relaxation, despite the fact the plasma ADMA levels are not increased (11).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Role of Dimethylarginine Dimethylaminohydrolases in the Regulation of Endothelial Nitric Oxide Production

Pope

Karrupiah

Kearns

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Reduced NO is a hallmark of endothelial dysfunction, and among the mechanisms for impaired NO synthesis is the accumulation of the endogenous nitric-oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Free ADMA is actively metabolized by the intracellular enzyme dimethylarginine dimethylaminohydrolase (DDAH), which catalyzes the conversion of ADMA to citrulline. Decreased DDAH expression/activity is evident in disease states associated with endothelial dysfunction and is believed to be the mechanism responsible for increased methylarginines and subsequent ADMA-mediated endothelial nitric-oxide synthase impairment. Two isoforms of DDAH have been identified; however, it is presently unclear which is responsible for endothelial ADMA metabolism and NO regulation. The current study investigated the effects of both DDAH-1 and DDAH-2 in the regulation of methylarginines and endothelial NO generation. Results demonstrated that overexpression of DDAH-1 and DDAH-2 increased endothelial NO by 24 and 18%, respectively. Moreover, small interfering RNA-mediated down-regulation of DDAH-1 and DDAH-2 reduced NO bioavailability by 27 and 57%, respectively. The reduction in NO production following DDAH-1 gene silencing was associated with a 48% reduction in L-Arg/ADMA and was partially restored with L-Arg supplementation. In contrast, L-Arg/ADMA was unchanged in the DDAH-2-silenced cells, and L-Arg supplementation had no effect on NO. These results clearly demonstrate that DDAH-1 and DDAH-2 manifest their effects through different mechanisms, the former of which is largely ADMA-dependent and the latter ADMA-independent. Overall, the present study demonstrates an important regulatory role for DDAH in the maintenance of endothelial function and identifies this pathway as a potential target for treating diseases associated with decreased NO bioavailability. Endothelium-derived nitric oxide (NO)2 is a potent vasodilator that plays a critical role in maintaining vascular homeostasis through its antiatherogenic and antiproliferative effects on the vascular wall. Altered NO biosynthesis has been implicated in the pathogenesis of cardiovascular disease, and evidence from animal models and clinical studies suggests that accumulation of the endogenous nitric-oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and N Gmethyl-L-arginine (L-NMMA) contribute to reduced NO generation and disease pathogenesis (1, 2). ADMA and L-NMMA are derived from the proteolysis of methylated arginine residues on various proteins. The methylation is carried out by a group of enzymes referred to as protein-arginine methyltransferases (3). Protein arginine methylation has been identified as an important post-translational modification involved in the regulation of DNA transcription, protein function, and cell signaling (4, 5). Upon proteolysis of methylated proteins, free methylarginines are released and can function as competitive inhibitors of NOS activity. The intracellular levels of these free methylarginines are regulated through the...

show abstract

Isoform-Specific Regulation by N ^G , N ^G -Dimethylarginine Dimethylaminohydrolase of Rat Serum Asymmetric Dimethylarginine and Vascular Endothelium-Derived Relaxing Factor/NO

Cited by 131 publications

References 27 publications

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Genetic variation in the dimethylarginine dimethylaminohydrolase 1 gene (DDAH1) is related to asymmetric dimethylarginine (ADMA) levels, but not to endothelium-dependent vasodilation

Role of Dimethylarginine Dimethylaminohydrolases in the Regulation of Endothelial Nitric Oxide Production

Contact Info

Product

Resources

About

Isoform-Specific Regulation by N G , N G -Dimethylarginine Dimethylaminohydrolase of Rat Serum Asymmetric Dimethylarginine and Vascular Endothelium-Derived Relaxing Factor/NO

Cited by 131 publications

References 27 publications

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Genetic variation in the dimethylarginine dimethylaminohydrolase 1 gene (DDAH1) is related to asymmetric dimethylarginine (ADMA) levels, but not to endothelium-dependent vasodilation

Role of Dimethylarginine Dimethylaminohydrolases in the Regulation of Endothelial Nitric Oxide Production

Contact Info

Product

Resources

About

Isoform-Specific Regulation by N ^G , N ^G -Dimethylarginine Dimethylaminohydrolase of Rat Serum Asymmetric Dimethylarginine and Vascular Endothelium-Derived Relaxing Factor/NO