Insulin and adiponectin inhibit the TNFα-induced ADMA accumulation in human endothelial cells

Eid, H.M.A.; Lyberg, Torstein; Arnesen, Harald; Seljeflot, Ingebjørg

doi:10.1016/j.atherosclerosis.2006.11.008

Cited by 42 publications

(29 citation statements)

References 36 publications

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“…This decreased accumulation of ADMA was accompanied by a dose-related increase in the activity of the metabolic enzyme dimethylarginine dimethylaminohydrolase. 43 These observations are thus in line with the present finding of an inverse relation between insulin and ADMA.…”

Section: Discussionsupporting

confidence: 82%

Brachial Artery Flow-Mediated Dilation and Asymmetrical Dimethylarginine in the Cardiovascular Risk in Young Finns Study

et al. 2007

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Background-Elevated asymmetrical dimethylarginine (ADMA) is a novel risk factor for atherosclerosis that may impair endothelial function by interfering with endothelial nitric oxide synthesis. To gain insight into the effects of ADMA on systemic endothelial function, we examined the association between ADMA and brachial artery flow-mediated dilation (FMD) in a large population of young adults. Methods and Results-Plasma ADMA and brachial FMD, as well as conventional cardiovascular risk factors, were measured in 2096 white adults aged 24 to 39 years. In univariate analysis, ADMA was inversely correlated with FMD (rϭϪ0.07, Pϭ0.003). The inverse association between ADMA and FMD remained significant in a multivariable regression model adjusted for age, sex, conventional cardiovascular risk factors, estimated glomerular filtration rate, and brachial artery baseline diameter (␤ϮSE Ϫ1.56Ϯ0.62%, Pϭ0.01). Conclusions-We conclude that elevated plasma ADMA concentrations are associated with decreased brachial FMD responses in healthy adults. These data provide evidence at the population level that ADMA levels are associated with endothelial function.

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Section: Discussionsupporting

confidence: 82%

Brachial Artery Flow-Mediated Dilation and Asymmetrical Dimethylarginine in the Cardiovascular Risk in Young Finns Study

et al. 2007

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“…Previous studies have shown that the loss of DDAH activity can augment the levels of cytokines, such as IL-1, IL-6, IL-8, and MCP-1 (28,47), and therefore potentiate inflammation. LPS-induced cytokines, such as TNF-a, have also been shown to decrease DDAH activity and enhance ADMA levels (28,48), providing a possible mechanism by which LPS regulates the DDAH/ADMA cascade. In our study, we analyzed a profile of 32 cytokines/chemokines in the BALF of mice treated with LPS, and found an increase in 28 of these cytokines, including IL-1, IL-6, MCP-1, and TNF-a (Table E1).…”

Section: Cd4/cd8mentioning

confidence: 99%

Dimethylarginine Dimethylaminohydrolase II Overexpression Attenuates LPS-Mediated Lung Leak in Acute Lung Injury

Aggarwal

Groß

Kumar

et al. 2014

Am J Respir Cell Mol Biol

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Acute lung injury (ALI) is a severe hypoxemic respiratory insufficiency associated with lung leak, diffuse alveolar damage, inflammation, and loss of lung function. Decreased dimethylaminohydrolase (DDAH) activity and increases in asymmetric dimethylarginine (ADMA), together with exaggerated oxidative/nitrative stress, contributes to the development of ALI in mice exposed to LPS. Whether restoring DDAH function and suppressing ADMA levels can effectively ameliorate vascular hyperpermeability and lung injury in ALI is unknown, and was the focus of this study. In human lung microvascular endothelial cells, DDAH II overexpression prevented the LPS-dependent increase in ADMA, superoxide, peroxynitrite, and protein nitration. DDAH II also attenuated the endothelial barrier disruption associated with LPS exposure. Similarly, in vivo, we demonstrated that the targeted overexpression of DDAH II in the pulmonary vasculature significantly inhibited the accumulation of ADMA and the subsequent increase in oxidative/nitrative stress in the lungs of mice exposed to LPS. In addition, augmenting pulmonary DDAH II activity before LPS exposure reduced lung vascular leak and lung injury and restored lung function when DDAH activity was increased after injury. Together, these data suggest that enhancing DDAH II activity may prove a useful adjuvant therapy to treat patients with ALI.

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“…Results from prospective studies reporting that high levels of ADMA predicted CV events in patients with diabetes mellitus (9,10) could not be confirmed in populationbased prospective cohorts (7). A possible explanation for these conflicting results may be that activity of the enzyme responsible for degradation of ADMA, dimethylarginine dimethylaminohydrolase (DDAH), is influenced by diabetes and diabetes therapy (11,12). Variation in the DDAH1 and/or DDAH2 genes were associated with differences in ADMA levels in diabetes subjects (13) and with insulin sensitivity in nondiabetic subjects (14) and predicted major CV events in diabetes subjects (15).…”

mentioning

confidence: 74%

Genetic and Environmental Determinants of Dimethylarginines and Association With Cardiovascular Disease in Patients With Type 2 Diabetes

et al. 2014

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OBJECTIVETo investigate determinants of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), including single nucleotide polymorphisms (SNPs), in the DDAH1, DDAH2, and AGXT2 genes and their associations with prevalent and incident cardiovascular disease (CVD) in older adults with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODSPrevalent CVD was assessed in men and women aged 60-75 years with type 2 diabetes as part of the Edinburgh Type 2 Diabetes Study (ET2DS), and the participants were prospectively followed up for 4 years for incident CVD. Dimethylarginines were measured in 783 of these subjects, and genotyping for tag SNPs in the DDAH1, DDAH2, and AGXT2 genes was performed in 935 subjects. RESULTSPlasma ADMA levels were significantly associated with SNPs in DDAH1 (top SNP rs1554597; P = 9.0E-09), while SDMA levels were associated with SNPs in AGXT2 (top SNP rs28305; P = 1.3E-04). Significant, independent determinants of plasma ADMA were sex, L-arginine, creatinine, fasting glucose, and rs1554597 (all P < 0.05; combined R 2 = 0.213). Determinants of SDMA were age, sex, creatinine, L-arginine, diabetes duration, prevalent CVD, and rs28305 (all P < 0.05; combined R 2 = 0.425). Neither dimethylarginine was associated with incident CVD. None of the investigated SNPs were associated with overall CVD, although subgroup analysis revealed a significant association of AGXT2 rs28305 with intermittent claudication. CONCLUSIONSOur study in a well-characterized population with type 2 diabetes does not support reported associations or causal relationship between ADMA and features of diabetes or CVD.

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Insulin and adiponectin inhibit the TNFα-induced ADMA accumulation in human endothelial cells

Cited by 42 publications

References 36 publications

Brachial Artery Flow-Mediated Dilation and Asymmetrical Dimethylarginine in the Cardiovascular Risk in Young Finns Study

Brachial Artery Flow-Mediated Dilation and Asymmetrical Dimethylarginine in the Cardiovascular Risk in Young Finns Study

Dimethylarginine Dimethylaminohydrolase II Overexpression Attenuates LPS-Mediated Lung Leak in Acute Lung Injury

Genetic and Environmental Determinants of Dimethylarginines and Association With Cardiovascular Disease in Patients With Type 2 Diabetes

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