Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis

Dayoub, Hayan; Achan, Vinod; Adimoolam, Shanthi; Jacobi, Johannes; Stuehlinger, Marcus C.; Wang, Bing Yin; Tsao, Philip S.; Kimoto, Masumi; Vallance, Patrick; Patterson, Andrew J.; Cooke, John P.

doi:10.1161/01.cir.0000101924.04515.2e

Cited by 318 publications

(271 citation statements)

References 53 publications

(37 reference statements)

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“…After acclimatization, animals were transferred to our transgenic core facility to rederive the colony using embryo transfer. Offsprings were genotyped by PCR of DNA obtained from tail-snip biopsies using transgene-specific oligonucleotide primers as described earlier (7).…”

Section: Animalsmentioning

confidence: 99%

“…Briefly, all animals were trained on alternate days over a period of 2 wk to get accustomed to the device. Final measurements were performed before pump implantation and on days 2,3,7,14,21, and 28 after surgery. A total of 20 consecutive readings of systolic blood pressure (SBP) and heart rate were recorded and averaged.…”

Section: Blood Pressure Measurementsmentioning

confidence: 99%

“…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).…”

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confidence: 99%

“…Here we investigated the effects of ANG II infusion on ADMA levels in vivo in WT animals and DDAH1 transgenic (TG) mice that overexpress the human isoform of this enzyme (7). We hypothesized that ANG II-induced hypertension and target organ damage are associated with an elevation of plasma ADMA levels and that, if this holds true, mice overexpressing DDAH should be, in part, protected from ANG II-induced target organ damage.…”

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confidence: 99%

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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

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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 ...

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Section: Animalsmentioning

confidence: 99%

Section: Blood Pressure Measurementsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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

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“…Because the plasma levels of ADMA attained by treatment with ADMA were far less compared with that of L-arginine, 37 it may be reasonable that ADMA treatment does not affect NO production. The following lines of evidence further support the involvement of NOindependent mechanisms in the long-term vascular effects of ADMA.…”

Section: Involvement Of No-independent Mechanisms In Long-term Vasculmentioning

confidence: 99%

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

Suda

Tsutsui

Morishita

et al. 2004

ATVB

172

124

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Objective-Asymmetric dimethylarginine (ADMA) is widely believed to be an endogenous nitric oxide synthase (eNOS) inhibitor. However, in this study, we examined our hypothesis that the long-term vascular effects of ADMA are not mediated by inhibition of endothelial NO synthesis. Methods and Results-ADMA was infused in wild-type and eNOS-knockout (KO) mice by osmotic minipump for 4 weeks. In wild-type mice, long-term treatment with ADMA caused significant coronary microvascular lesions. Importantly, in eNOS-KO mice, treatment with ADMA also caused an extent of coronary microvascular lesions that was comparable to that in wild-type mice. These vascular effects of ADMA were not prevented by supplementation of L-arginine, and vascular NO production was not reduced by ADMA treatment. Treatment with ADMA caused upregulation of angiotensin-converting enzyme (ACE) and an increase in superoxide production that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or olmesartan (AT 1 receptor antagonist), which simultaneously suppressed vascular lesion formation. Key Words: asymmetric dimethylarginine Ⅲ arteriosclerosis Ⅲ nitric oxide Ⅲ endothelial nitric oxide synthase Ⅲ mice E ndothelium-derived nitric oxide (NO), synthesized from L-arginine by endothelial NO synthase (eNOS), has several important antiatherogenic actions. 1-5 Indeed, reduction of endothelial NO synthesis (endothelial dysfunction) predisposes the blood vessel to arteriosclerosis, 1-5 and the eNOS-deficient (eNOS-KO) mice exhibit accelerated vascular lesion formation. 6,7 As pharmacological tools to inhibit endothelial NO synthesis, synthetic L-arginine analogues have been used in vitro and in vivo. Among them, N -nitro-L-arginine methyl ester (L-NAME) is the most frequently used agent. [1][2][3][4][5] Long-term treatment with L-NAME is known to cause arteriosclerotic coronary lesions, especially at microvascular levels, in experimental animals. 8,9 This model with L-NAME is regarded as a useful animal model for examining the protective roles of endothelium-derived NO in the pathogenesis of arteriosclerosis. 8,9 See cover However, it is controversial whether these vascular effects of L-NAME are caused primarily by the inhibition of endothelial NO synthesis for the following reasons: first, the importance of endothelium-derived NO decreases as the vessel size becomes smaller, 10 whereas L-NAME-induced vascular lesions are prominent at microvascular levels; 8 second, long-term treatment with L-NAME does not reduce eNOS activity; 11 third, multiple actions of L-NAME other than simple inhibition of NO synthesis have been reported. 12,13 The most appropriate way to address this issue is to use mice that are deficient in the eNOS gene and to examine whether long-term treatment with L-NAME causes coronary vascular lesions in those mice. We have recently shown that treatment with L-NAME causes a comparable extent of Conclusions-These

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Elevated plasma asymmetric dimethyl‐L‐arginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis

Surdacki¹,

Martens‐Lobenhoffer²,

Włoch³

et al. 2007

Arthritis & Rheumatism

104

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Plasma asymmetric dimethyl-L-arginine levels are elevated in RA patients free of cardiovascular disease or risk factors. Asymmetric dimethyl-L-arginine accumulation may contribute to endothelial progenitor cell depletion via depressed NO-dependent endothelial progenitor cell mobilization and/or survival, with consequent impairment of endothelial progenitor cell-mediated endothelial repair, which can promote atherogenesis in RA.

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Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis

Cited by 318 publications

References 53 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

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

Elevated plasma asymmetric dimethyl‐L‐arginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis

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