Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine.

Department of Nephrology and Hypertension, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
American Journal Of Pathology (Impact Factor: 4.6). 03/2010; 176(5):2559-70. DOI: 10.2353/ajpath.2010.090614
Source: PubMed

ABSTRACT Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as a novel biomarker in cardiovascular disease. To date, it remains unclear whether elevated ADMA levels are merely associated with cardiovascular risk or whether this molecule is of functional relevance in the pathogenesis of atherosclerotic vascular disease. To clarify this issue, we crossed dimethylarginine dimethylaminohydrolase (DDAH) transgenic mice that overexpress the human isoform 1 of the ADMA degrading enzyme DDAH into ApoE-deficient mice to generate ApoE(-/-)/hDDAH1(+/-) mice. In these mice, as well as ApoE(-/-) wild-type littermates, atherosclerosis within the aorta as well as vascular function of aortic ring preparations was assessed. We report here that overexpression of hDDAH1 reduces plaque formation in ApoE(-/-) mice by lowering ADMA. The extent of atherosclerosis closely correlated with plasma ADMA levels in male but not female mice fed either a standard rodent chow or an atherogenic diet. Functional analysis of aortic ring preparations revealed improved endothelial function in mice overexpressing hDDAH1. Our findings provide proof-of-principle that ADMA plays a causal role as a culprit molecule in atherosclerosis and support recent evidence indicating a functional relevance of DDAH enzymes in genetic mouse models. Together, these results demonstrate that pharmacological interventions targeting the ADMA/DDAH pathway may represent a novel approach in the prevention and management of cardiovascular diseases.

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    ABSTRACT: Adult survivors of childhood malignancy are predisposed to late cardiovascular (CV) complications. Our aim was to estimate plasma levels of the endogenous nitric oxide formation inhibitor asymmetric dimethylarginine (ADMA), in long-term survivors of childhood acute lymphoblastic leukemia (ALL) treated with only chemotherapy. ADMA and its isomer symmetric dimethylarginine (SDMA) were measured in 25 former ALL patients (aged 18-28 years) who had survived without recurrent disease ≥ 5 years from completing chemotherapy without cranial irradiation, and in 20 healthy controls (aged 20-31 years). Characteristics of the both groups were similar, except for lower high-density lipoproteins-cholesterol (HDL-C) in ALL survivors. Compared to controls, the former ALL patients exhibited significant, albeit small, rises in levels of ADMA (0.63 ± 0.09 [SD] vs. 0.57 ± 0.07 μmol/L; p=0.016), but not SDMA, with a consequently increased ADMA to SDMA ratio (1.08 ± 0.22 vs. 0.91 ± 0.16; p=0.004). The effect of former ALL on ADMA was attenuated (intergroup p=0.10 [ANCOVA]) upon adjustment for HDL-C (ADMA vs. HDL-C regression coefficient: -0.065 ± 0.030 [SEM]; p=0.03). ADMA is elevated in adult childhood ALL survivors, which can reflect late detrimental chemotherapy effects, partially related to minor lipid profile changes. Whether these subtle ADMA elevations might herald future CV morbidity, remains to be elucidated.
    Disease markers 01/2012; 33(2):69-76. · 2.14 Impact Factor
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    ABSTRACT: BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor, which has been associated with total and cardiovascular mortality in various clinical settings. Studies on its structural isomer, symmetric dimethylarginine (SDMA), are scarce. This study aimed to determine the associations of both ADMA and SDMA levels with secondary cardiovascular disease events and all-cause mortality in patients with stable coronary heart disease (CHD). METHODS: In the observational prospective cohort study KAROLA, 1,148 CHD patients were followed for a median of 8.1 years. ADMA and SDMA were determined by liquid chromatography-tandem mass spectrometry. Baseline ADMA and SDMA levels were categorized in quartiles or standardized by their respective standard deviation, and appropriate hazard ratios and 95 % confidence intervals (HR [95 % CI]) were estimated in Cox proportional hazards models. RESULTS: 150 patients experienced secondary cardiovascular disease events (CVD) and 121 patients died. After adjustment for confounders, ADMA was not associated with the risk of secondary CVD events (HR per standard deviation increase: 1.02 [95 %CI: 0.86-1.21]), whereas an association was suggested for SDMA (HR 1.17 [1.00-1.37]). Higher hazard ratios were observed in all-cause mortality models (ADMA: HR 1.15 [0.95-1.37]; SDMA: HR 1.29 [1.09-1.52]). CONCLUSIONS: Our results suggest that especially SDMA might possibly have potential as a risk marker for all-cause mortality and to a lesser extent for secondary cardiovascular events. Future studies are needed to quantify these associations more precisely and should, in particular, further address the possibility of residual confounding by impaired kidney function.
    Clinical Research in Cardiology 10/2012; · 3.67 Impact Factor
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    ABSTRACT: The purpose of the work was to study the impact of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1), on atherosclerosis in subtotally nephrectomized (SNX) ApoE-deficient mice. Male DDAH1 transgenic mice (TG, n = 39) and C57Bl/6J wild-type littermates (WT, n = 27) with or without the deletion of the ApoE gene underwent SNX at the age of eight weeks. Animals were sacrificed at 12 months of age, and blood chemistry, as well as the extent of atherosclerosis within the entire aorta were analyzed. Sham treated (no renal mass reduction) ApoE-competent DDAH1 transgenic and wild-type littermates (n = 11) served as a control group. Overexpression of DDAH1 was associated with significantly lower ADMA levels in all treatment groups. Surprisingly, SNX mice did not exhibit higher ADMA levels compared to sham treated control mice. Furthermore, the degree of atherosclerosis in ApoE-deficient mice with SNX was similar in mice with or without overexpression of DDAH1. Overexpression of the ADMA degrading enzyme, DDAH1, did not ameliorate atherosclerosis in ApoE-deficient SNX mice. Furthermore, SNX in mice had no impact on ADMA levels, suggesting a minor role of this molecule in chronic kidney disease (CKD) in this mouse model.
    International Journal of Molecular Sciences 01/2014; 15(4):5522-35. · 2.46 Impact Factor


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