Article

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.
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.

0 Bookmarks
 · 
155 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abdominal vascular lesions are amongst the most lethal lesions suffered by patients with multiple injuries, as well as being among the most difficult and challenging for the surgeon. They are rarely isolated, they are usually found with associated multiple injuries, which increases its seriousness and the time required to repair them and may lead to a significant morbidity and mortality. The correct management involves an early diagnosis and surgical approach.
    Cirugía Española 04/2012; · 0.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute and sustained hypoxic pulmonary vasoconstriction (HPV), as well as chronic pulmonary hypertension (PH) is modulated by nitric oxide (NO). NO synthesis can be decreased by asymmetric dimethylarginine (ADMA), which is degraded by dimethylarginine dimethylaminohydrolase 1 (DDAH1). We investigated the effect of DDAH1 overexpression (DDAH1tg) on HPV and chronic hypoxia-induced PH. HPV was measured during acute (10 minutes) and sustained (3 hours) hypoxia in isolated mouse lungs. Chronic PH was induced by exposure of mice to 4 weeks of hypoxia. ADMA and cyclic 3', 5'-guanosine monophophate (cGMP) were determined by ELISA and NO generation by chemiluminescence. DDAH1 overexpression had no effects on acute HPV. However, DDAH1tg mice showed decreased sustained HPV compared to wild type (WT) mice. Concomitantly, ADMA was decreased, and levels of NO and cGMP were significantly increased in DDAH1tg. Administration of either Nω-Nitro-L-arginine (L-NNA) or 1H-[1, 2, 4]oxadiazolo [4, 3-a] quinoxalin-1-one (ODQ) potentiated sustained HPV and partially abolished the differences of sustained HPV between WT and DDAH1tg mice. Overexpression of DDAH1 had no effect on development of chronic hypoxia-induced PH. DDAH1 overexpression selectively decreased the sustained phase of HPV, partially via activation of the NO-cGMP pathway. Thus, increased ADMA levels modulate sustained HPV, but not acute HPV or chronic hypoxia-induced PH.
    American Journal of Respiratory Cell and Molecular Biology 05/2013; · 4.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 04/2014; 15(4):5522-35. · 2.34 Impact Factor

Preview

Download
3 Downloads
Available from