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. 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.

0 Bookmarks
 · 
143 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.
    Cirugia Espanola - CIR ESPAN. 04/2012;
  • 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 01/2014; 15(4):5522-35. · 2.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthesis inhibitor, and insulin resistance (IR) have been implicated in atherogenesis. Our aim was to estimate relations between ADMA, the magnitude of IR and angiographic indices of extent and severity of coronary atherosclerosis in non-diabetic men with stable coronary artery disease (CAD). We studied 151 non-diabetic men (mean age 57 +/- 11 years) with stable angina, obstructive CAD (at least 1 luminal diameter stenosis of >=70% in major coronary segments) and without heart failure, and 34 age-matched controls free of >=50% coronary narrowings. The following CAD indices were computed: the number of major epicardial vessels with >=70% stenosis, Sullivan extent score representing a proportion of the visible coronary tree with vessel wall irregularities, and Gensini score which reflects both CAD severity and extent, yet assigning a heavier weight to proximal segments and to the more severe narrowings by a non-linear point system. An estimate of IR was derived by homeostasis model assessment (HOMA-IR) from fasting insulin and glucose. Among the CAD patients, the proportions of subjects with 1-vessel, 2- vessel and 3-vessel CAD were 26%, 25% and 49%, respectively. ADMA levels were higher in patients with obstructive CAD compared to the controls (0.51 +/- 0.10 vs. 0.46 +/- 0.09 mumol/L [SD], P = 0.01), whereas HOMA-IR was similar (median, 3.2 [interquartile range: 2.4--4.9] vs. 2.9 [2.3--4.7], P = 0.2). Within the CAD group, ADMA increased across ascending quartiles of Sullivan score (Spearman's rho = 0.23, P = 0.004), but not with Gensini score (rho = 0.12, P = 0.15) or the number of vessels involved (rho = 0.08, P = 0.3). ADMA correlated to log-transformed Sullivan score (r = 0.21, P = 0.008), which was only slightly attenuated upon multivariate adjustment (beta = 0.19 +/- 0.08 [SEM], P = 0.015). HOMA-IR did not differ according to any measure of angiographic CAD (P >= 0.2). ADMA and log(HOMA-IR) were mutually unrelated (r = 0.07, P = 0.4). ADMA is associated with diffuse but not focal coronary atherosclerosis in non-diabetic men with stable CAD irrespectively of the degree of IR. The independent relationship between ADMA and coronary atherosclerotic burden may contribute to the well-recognized prognostic effect of ADMA in CAD.
    Cardiovascular Diabetology 10/2013; 12(1):145. · 4.21 Impact Factor

Full-text

Download
3 Downloads
Available from