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Rainer H Boger - One of the best experts on this subject based on the ideXlab platform.
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higher serum asymmetric Dimethylarginine is related to higher risk of heart failure in the epic potsdam study
Amino Acids, 2017Co-Authors: Janine Wirth, Dorothee Atzler, Rainer H Boger, Romina Di Giuseppe, Kathrin Cordts, Juliane Menzel, Heiner Boeing, Cornelia Weikert, Edzard SchwedhelmAbstract:l-Arginine is the substrate of endothelial nitric oxide (NO) synthase forming NO which inherits various biological cardio-protective functions. The Dimethylarginines asymmetric (ADMA) and symmetric Dimethylarginine (SDMA) can impair the synthesis of NO and are elevated in patients with cardiovascular disease, including heart failure (HF). We investigated the association between Dimethylarginines and HF risk in a case-cohort study of the European Prospective Investigation into Cancer and Nutrition (n = 27,548), comprising a random subcohort (n = 2224 including 19 HF cases), and all remaining HF cases (n = 176) that occurred within 8.3 years of follow-up. Serum concentrations of Dimethylarginines were measured using liquid chromatography-tandem mass spectrometry. Hazards ratios (HRs) and 95% confidence intervals (CI) were estimated across quartiles and per doubling of ADMA and SDMA concentrations using Cox’s proportional hazards regression. After multivariable adjustment, each doubling of ADMA was associated with a 60% higher HF risk (HR [95% CI] 1.60 [1.10–2.31]). Between SDMA and HF risk a U-shaped association was observed (HR [95% CI] for the second, third and fourth quartile compared to the first: 0.52 [0.33–0.82], 0.63 [0.40–0.99], and 0.71 [0.46–1.10], p for nonlinearity <0.01). We provide substantiated evidence for a relationship between ADMA and cardiovascular endpoints. In addition to the established relation between ADMA and myocardial infarction, our findings indicate a positive association between ADMA and HF incidence in persons without apparent myocardial infarction. Targeting the ADMA metabolism might open up new therapeutic perspective for HF prevention and treatment. Further investigations are needed to shed more light on mechanisms involved in the pathogenesis of HF related to elevated ADMA levels.
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Nitric oxide synthesis capacity, ambulatory blood pressure and end organ damage in a black and white population: the SABPA study
Amino Acids, 2016Co-Authors: Catharina M. C. Mels, Ilisma Loots, Dorothee Atzler, Edzard Schwedhelm, Rainer H Boger, Aletta E SchutteAbstract:Nitric oxide (NO) synthesis capacity is determined by the availability of substrate(s) such as l -arginine and the influence of nitric oxide synthase (NOS) inhibitors, asymmetric Dimethylarginine (ADMA) and symmetric Dimethylarginine (SDMA). These factors may be important in black South Africans with a very high prevalence of hypertension. We compared ambulatory blood pressure (BP), markers of end organ damage and NO synthesis capacity markers [ l -arginine, l -homoarginine, l -citrulline, l -arginine:ADMA, ADMA, SDMA and Dimethylarginine (DMA)], between black and white teachers ( n = 390). Associations of nighttime BP and markers of end organ damage with NO synthesis capacity markers were also investigated. Although black men and women had higher BP and albumin-to-creatinine ratio (ACR) (all p
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Dimethylarginines, homocysteine metabolism, and cerebrospinal fluid markers for Alzheimer's disease.
Journal of Alzheimer's disease : JAD, 2012Co-Authors: Sönke Arlt, Edzard Schwedhelm, Rainer H Boger, Heike Kölsch, Holger Jahn, Michael Linnebank, Yvo M. Smulders, Frank Jessen, Julius PoppAbstract:Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and Dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and Dimethylarginine metabolism (plasma and CSF asymmetric Dimethylarginine (ADMA), symmetric Dimethylarginine, L-arginine) as well as CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis.
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The role of asymmetric and symmetric Dimethylarginines in renal disease
Nature reviews. Nephrology, 2011Co-Authors: Edzard Schwedhelm, Rainer H BogerAbstract:Asymmetric Dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is a marker of renal dysfunction progression, vascular complications and death. Levels of ADMA and levels of its isomer symmetric Dimethylarginine (SDMA) are elevated in patients with kidney disease. In this Review, Schwedhelm and Boger provide an overview of the roles of both Dimethylarginines in renal, cerebrovascular and cardiovascular disease, and discuss how the biological function of ADMA and SDMA could be targeted to treat renal disease in the future. Asymmetric Dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases. By inhibiting nitric oxide formation, ADMA causes endothelial dysfunction, vasoconstriction, elevation of blood pressure, and aggravation of experimental atherosclerosis. Levels of ADMA and its isomer symmetric Dimethylarginine (SDMA), which does not inhibit nitric oxide synthesis, are both elevated in patients with kidney disease. Currently available data from prospective clinical trials in patients with chronic kidney disease suggest that ADMA is an independent marker of progression of renal dysfunction, vascular complications and death. High SDMA levels also negatively affect survival in populations at increased cardiovascular risk, but the mechanisms underlying this effect are currently only partly understood. Beyond glomerular filtration, other factors influence the plasma concentrations of ADMA and SDMA. Elevated plasma concentrations of these Dimethylarginines might also indirectly influence the activity of nitric oxide synthases by inhibiting the uptake of cellular L-arginine. Other mechanisms may exist by which SDMA exerts its biological activity. The biochemical pathways that regulate ADMA and SDMA, and the pathways that transduce their biological function, could be targeted to treat renal disease in the future.
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Role of asymmetric Dimethylarginine for angiotensin II-induced target organ damage in mice
American journal of physiology. Heart and circulatory physiology, 2007Co-Authors: Johannes Jacobi, Rainer H Boger, Renke Maas, Nada Cordasic, Kilian Koch, Roland E. Schmieder, Karl F. HilgersAbstract: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 dimethylamino...
Edzard Schwedhelm - One of the best experts on this subject based on the ideXlab platform.
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Asymmetric Dimethylarginine and symmetric Dimethylarginine prospectively relates to carotid wall thickening in black men: the SABPA study
Amino Acids, 2017Co-Authors: Catharina M. C. Mels, Dorothee Atzler, Edzard Schwedhelm, A. E. Schutte, H. W. Huisman, W. Smith, R. Kruger, J. M. Rooyen, R. H. Böger, N. T. MalanAbstract:The relationship of both asymmetric (ADMA) and symmetric (SDMA) Dimethylarginine with carotid wall thickness is inconclusive especially among black populations. We aimed to compare carotid intima media thickness (cIMT) and Dimethylarginine levels in 75 black and 91 white men at baseline and after a 3-year follow-up, and to investigate associations of percentage change in cIMT with percentage change in Dimethylarginine levels (ADMA and SDMA). Plasma levels of ADMA and SDMA were determined with a liquid chromatography mass spectrometry method and B-mode ultrasonography was used to determine the cIMT at baseline and follow-up. In black men, mean cIMT ( p = 0.79) and ADMA levels ( p = 0.67) remained the same, but SDMA levels were lower ( p
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higher serum asymmetric Dimethylarginine is related to higher risk of heart failure in the epic potsdam study
Amino Acids, 2017Co-Authors: Janine Wirth, Dorothee Atzler, Rainer H Boger, Romina Di Giuseppe, Kathrin Cordts, Juliane Menzel, Heiner Boeing, Cornelia Weikert, Edzard SchwedhelmAbstract:l-Arginine is the substrate of endothelial nitric oxide (NO) synthase forming NO which inherits various biological cardio-protective functions. The Dimethylarginines asymmetric (ADMA) and symmetric Dimethylarginine (SDMA) can impair the synthesis of NO and are elevated in patients with cardiovascular disease, including heart failure (HF). We investigated the association between Dimethylarginines and HF risk in a case-cohort study of the European Prospective Investigation into Cancer and Nutrition (n = 27,548), comprising a random subcohort (n = 2224 including 19 HF cases), and all remaining HF cases (n = 176) that occurred within 8.3 years of follow-up. Serum concentrations of Dimethylarginines were measured using liquid chromatography-tandem mass spectrometry. Hazards ratios (HRs) and 95% confidence intervals (CI) were estimated across quartiles and per doubling of ADMA and SDMA concentrations using Cox’s proportional hazards regression. After multivariable adjustment, each doubling of ADMA was associated with a 60% higher HF risk (HR [95% CI] 1.60 [1.10–2.31]). Between SDMA and HF risk a U-shaped association was observed (HR [95% CI] for the second, third and fourth quartile compared to the first: 0.52 [0.33–0.82], 0.63 [0.40–0.99], and 0.71 [0.46–1.10], p for nonlinearity <0.01). We provide substantiated evidence for a relationship between ADMA and cardiovascular endpoints. In addition to the established relation between ADMA and myocardial infarction, our findings indicate a positive association between ADMA and HF incidence in persons without apparent myocardial infarction. Targeting the ADMA metabolism might open up new therapeutic perspective for HF prevention and treatment. Further investigations are needed to shed more light on mechanisms involved in the pathogenesis of HF related to elevated ADMA levels.
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Nitric oxide synthesis capacity, ambulatory blood pressure and end organ damage in a black and white population: the SABPA study
Amino Acids, 2016Co-Authors: Catharina M. C. Mels, Ilisma Loots, Dorothee Atzler, Edzard Schwedhelm, Rainer H Boger, Aletta E SchutteAbstract:Nitric oxide (NO) synthesis capacity is determined by the availability of substrate(s) such as l -arginine and the influence of nitric oxide synthase (NOS) inhibitors, asymmetric Dimethylarginine (ADMA) and symmetric Dimethylarginine (SDMA). These factors may be important in black South Africans with a very high prevalence of hypertension. We compared ambulatory blood pressure (BP), markers of end organ damage and NO synthesis capacity markers [ l -arginine, l -homoarginine, l -citrulline, l -arginine:ADMA, ADMA, SDMA and Dimethylarginine (DMA)], between black and white teachers ( n = 390). Associations of nighttime BP and markers of end organ damage with NO synthesis capacity markers were also investigated. Although black men and women had higher BP and albumin-to-creatinine ratio (ACR) (all p
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Genome-Wide Association Study of l-Arginine and Dimethylarginines Reveals Novel Metabolic Pathway for Symmetric Dimethylarginine
Circulation. Cardiovascular genetics, 2014Co-Authors: Nicole Lüneburg, Edzard Schwedhelm, Renke Maas, Wolfgang Lieb, Tanja Zeller, Ming-huei Chen, Angela M. Carter, Vanessa Xanthakis, Nicole L. Glazer, Sudha SeshadriAbstract:Background—Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA ...
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Dimethylarginines, homocysteine metabolism, and cerebrospinal fluid markers for Alzheimer's disease.
Journal of Alzheimer's disease : JAD, 2012Co-Authors: Sönke Arlt, Edzard Schwedhelm, Rainer H Boger, Heike Kölsch, Holger Jahn, Michael Linnebank, Yvo M. Smulders, Frank Jessen, Julius PoppAbstract:Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and Dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and Dimethylarginine metabolism (plasma and CSF asymmetric Dimethylarginine (ADMA), symmetric Dimethylarginine, L-arginine) as well as CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis.
Annalise E Zemlin - One of the best experts on this subject based on the ideXlab platform.
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The cardiovascular risk marker asymmetric Dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression.
Annals of clinical biochemistry, 2013Co-Authors: Careen L Hudson, Annalise E ZemlinAbstract:As lifespan in HIV infection increases, cardiovascular disease has emerged as a cause of morbidity and mortality. Asymmetric Dimethylarginine is an established marker of endothelial dysfunction and predicts cardiovascular events. The role of asymmetric Dimethylarginine in HIV-related cardiovascular disease has not been established. Our aim was to determine whether asymmetric Dimethylarginine concentrations were elevated in treatment naïve, HIV-infected subjects and to correlate these with markers of immune activation and disease progression. Serum samples were collected from HIV-positive and -negative subjects attending a primary health care clinic over a 12-month period. Asymmetric Dimethylarginine concentrations were measured and correlated with CD4 count, viral load, hsCRP, IL-6, IgG, adenosine deaminase and CD8/38 T lymphocytes. Sixty HIV-positive participants (mean age 32.0 years) and 20 HIV-negative controls (mean age 32.4 years) were studied. All were of black ethnicity. The mean asymmetric Dimethylarginine concentration in the infected group measured 0.67 µmol/L (95% CI 0.62-0.72 µmol/L) which was significantly higher than in the control group of 0.48 µmol/L (95% CI 0.40-0.56 µmol/L). Asymmetric Dimethylarginine correlated inversely with CD4 counts and positively with IgG, adenosine deaminase and CD8/38 T lymphocytes. No significant correlation was found with hsCRP, IL-6, or viral load. We demonstrated that asymmetric Dimethylarginine is elevated in HIV infection, in patients with relatively well-preserved CD4 counts not yet on anti-retroviral treatment. We showed significant correlations of asymmetric Dimethylarginine with CD8/38 T lymphocytes, IgG and adenosine deaminase, suggesting that T-cell activation and the adaptive immune response underlie asymmetric Dimethylarginine elevation in this population. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
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The cardiovascular risk marker asymmetric Dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression.
Annals of Clinical Biochemistry, 2013Co-Authors: Careen L Hudson, Annalise E ZemlinAbstract:BackgroundAs lifespan in HIV infection increases, cardiovascular disease has emerged as a cause of morbidity and mortality. Asymmetric Dimethylarginine is an established marker of endothelial dysfunction and predicts cardiovascular events. The role of asymmetric Dimethylarginine in HIV-related cardiovascular disease has not been established. Our aim was to determine whether asymmetric Dimethylarginine concentrations were elevated in treatment naive, HIV-infected subjects and to correlate these with markers of immune activation and disease progression.MethodsSerum samples were collected from HIV-positive and -negative subjects attending a primary health care clinic over a 12-month period. Asymmetric Dimethylarginine concentrations were measured and correlated with CD4 count, viral load, hsCRP, IL-6, IgG, adenosine deaminase and CD8/38 T lymphocytes.ResultsSixty HIV-positive participants (mean age 32.0 years) and 20 HIV-negative controls (mean age 32.4 years) were studied. All were of black ethnicity. The m...
Careen L Hudson - One of the best experts on this subject based on the ideXlab platform.
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The cardiovascular risk marker asymmetric Dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression.
Annals of clinical biochemistry, 2013Co-Authors: Careen L Hudson, Annalise E ZemlinAbstract:As lifespan in HIV infection increases, cardiovascular disease has emerged as a cause of morbidity and mortality. Asymmetric Dimethylarginine is an established marker of endothelial dysfunction and predicts cardiovascular events. The role of asymmetric Dimethylarginine in HIV-related cardiovascular disease has not been established. Our aim was to determine whether asymmetric Dimethylarginine concentrations were elevated in treatment naïve, HIV-infected subjects and to correlate these with markers of immune activation and disease progression. Serum samples were collected from HIV-positive and -negative subjects attending a primary health care clinic over a 12-month period. Asymmetric Dimethylarginine concentrations were measured and correlated with CD4 count, viral load, hsCRP, IL-6, IgG, adenosine deaminase and CD8/38 T lymphocytes. Sixty HIV-positive participants (mean age 32.0 years) and 20 HIV-negative controls (mean age 32.4 years) were studied. All were of black ethnicity. The mean asymmetric Dimethylarginine concentration in the infected group measured 0.67 µmol/L (95% CI 0.62-0.72 µmol/L) which was significantly higher than in the control group of 0.48 µmol/L (95% CI 0.40-0.56 µmol/L). Asymmetric Dimethylarginine correlated inversely with CD4 counts and positively with IgG, adenosine deaminase and CD8/38 T lymphocytes. No significant correlation was found with hsCRP, IL-6, or viral load. We demonstrated that asymmetric Dimethylarginine is elevated in HIV infection, in patients with relatively well-preserved CD4 counts not yet on anti-retroviral treatment. We showed significant correlations of asymmetric Dimethylarginine with CD8/38 T lymphocytes, IgG and adenosine deaminase, suggesting that T-cell activation and the adaptive immune response underlie asymmetric Dimethylarginine elevation in this population. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
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The cardiovascular risk marker asymmetric Dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression.
Annals of Clinical Biochemistry, 2013Co-Authors: Careen L Hudson, Annalise E ZemlinAbstract:BackgroundAs lifespan in HIV infection increases, cardiovascular disease has emerged as a cause of morbidity and mortality. Asymmetric Dimethylarginine is an established marker of endothelial dysfunction and predicts cardiovascular events. The role of asymmetric Dimethylarginine in HIV-related cardiovascular disease has not been established. Our aim was to determine whether asymmetric Dimethylarginine concentrations were elevated in treatment naive, HIV-infected subjects and to correlate these with markers of immune activation and disease progression.MethodsSerum samples were collected from HIV-positive and -negative subjects attending a primary health care clinic over a 12-month period. Asymmetric Dimethylarginine concentrations were measured and correlated with CD4 count, viral load, hsCRP, IL-6, IgG, adenosine deaminase and CD8/38 T lymphocytes.ResultsSixty HIV-positive participants (mean age 32.0 years) and 20 HIV-negative controls (mean age 32.4 years) were studied. All were of black ethnicity. The m...
Masumi Kimoto - One of the best experts on this subject based on the ideXlab platform.
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role of asymmetric Dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2
Circulation Research, 2007Co-Authors: Kazuhiro Hasegawa, Koichiro Homma, Naoki Sugano, Masumi Kimoto, Shu Wakino, Kyoko Yoshioka, Satoru Tatematsu, Koichi Hayashi, Hiroshi ItohAbstract:Dimethylarginie dimethylaminohydrolase (DDAH) degrades asymmetric Dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, and comprises 2 isoforms, DDAH1 and DDAH2. To investig...
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role of asymmetric Dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2
Circulation Research, 2007Co-Authors: Kazuhiro Hasegawa, Koichiro Homma, Naoki Sugano, Masumi Kimoto, Shu Wakino, Kyoko Yoshioka, Satoru Tatematsu, Koichi Hayashi, Hiroshi ItohAbstract:Dimethylarginie dimethylaminohydrolase (DDAH) degrades asymmetric Dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, and comprises 2 isoforms, DDAH1 and DDAH2. To investigate the in vivo role of DDAH2, we generated trangenic mice overexpressing DDAH2. The transgenic mice manifested reductions in plasma ADMA and elevations in cardiac NO levels but no changes in systemic blood pressure (SBP), compared with the wild-type mice. When infused into wild-type mice for 4 weeks, ADMA elevated SBP and caused marked medial thickening and perivascular fibrosis in coronary microvessels, which were accompanied by ACE protein upregulation and cardiac oxidative stress. The treatment with amlodipine reduced SBP but failed to ameliorate the ADMA-induced histological changes. In contrast, these changes were abolished in transgenic mice, with a reduction in plasma ADMA. In coronary artery endothelial cells, ADMA activated p38 MAP kinase and the ADMA-induced ACE upregulation was suppressed by p38 MAP ...
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Dimethylarginine dimethylaminohydrolase 2 increases vascular endothelial growth factor expression through sp1 transcription factor in endothelial cells
Arteriosclerosis Thrombosis and Vascular Biology, 2006Co-Authors: Kazuhiro Hasegawa, Takeshi Kanda, Koichiro Homma, Naoki Sugano, Masumi Kimoto, Shu Wakino, Kyoko Yoshioka, Satoru Tatematsu, Toru Tanaka, Masahiko KurabayashiAbstract:Objectives— Dimethylarginie dimethylaminohydrolase (DDAH) is a degrading enzyme for asymmetrical Dimethylarginine, an endogenous NO synthase inhibitor. The molecular mechanism for DDAH-induced vascular endothelial growth factor (VEGF) expression was examined. Methods and Results— Although the transfection of expression vectors for 2 isoforms of DDAH, DDAH1, or DDAH2 increased DDAH activity in bovine aortic endothelial cells and human umbilical vein endothelial cells, expression and secretion of VEGF were increased only in DDAH2-transfected cells. Knocking down the DDAH2 gene reduced VEGF production, and DDAH2 overexpression enhanced both proliferation and migration of endothelial cells. The VEGF promoter activity was increased by DDAH2 transfection, which was not blocked by an NO synthase (NOS) inhibitor but required the Sp1 sites. DDAH2 overexpression increased nuclear protein levels bound to Sp1 oligonucleotides in endothelial cells. Sp1 small interfering RNA blocked DDAH2-induced upregulation of VEGF. DDAH2 transfection increased nuclear and threonine-phosphorylation levels of Sp1 in a protein kinase A (PKA)–dependent manner. Protein–protein interaction between DDAH2 and PKA was enhanced in DDAH2-transfected cells. Conclusions— DDAH2 upregulated the expression of VEGF through Sp1-dependent and NO/NOS system-independent promoter activation. DDAH2-increased Sp1 DNA binding activity was PKA dependent. These mechanisms may provide a novel therapeutic strategy for VEGF-related vasculopathies such as atherosclerosis.
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Purification, cDNA cloning and expression of human NG,NG‐Dimethylarginine dimethylaminohydrolase
European journal of biochemistry, 1998Co-Authors: Masumi Kimoto, Tadashi Ogawa, Satoko Miyatake, Takayo Sasagawa, Hiromi Yamashita, Misako Okita, Tatsuzou Oka, Hideaki TsujiAbstract:cDNA encoding N(G),N(G)-Dimethylarginine dimethylaminohydrolase from rat kidney had been cloned [Kimoto, M., Sasakawa, T., Tsuji, H., Miyatake, S., Oka, T., Nio, N. & Ogawa, T. (1997) Biochim. Biophys. Acta 1337, 6-10]. The enzyme hydrolyzes N(G),N(G)-dimethyl-L-arginine and N(G)-monomethyl-L-arginine, which are known as endogenous inhibitors for the nitric oxide-generating system. In the present study, human N(G),N(G)-Dimethylarginine dimethylaminohydrolase has been purified to homogeneity from liver and characterized. The cDNA clone encoding human N(G),N(G)-Dimethylarginine dimethylaminohydrolase was isolated from a human kidney lambda gt10 library using a probe prepared from a plasmid containing the entire coding region of rat N(G),N(G)-Dimethylarginine dimethylaminohydrolase. Its open reading frame encoded a protein of 285 amino acids with a molecular mass of 31,121 Da. The deduced amino acid sequence exhibits 93% identity with that of rat. The cDNA was expressed as a fusion protein in Escherichia coli and the recombinant protein exhibited enzyme activity which is the same as that of natural enzyme.
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Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney
Kidney International, 1997Co-Authors: Akihiro Tojo, Patrick Vallance, Viviane Bremer, Masumi Kimoto, Tadashi Ogawa, Masao Omata, Kenjiro Kimura, William J. Welch, Christopher S. WilcoxAbstract:Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. N G -monomethylarginine (L-NMA) and asymmetric N G , N G -Dimethylarginines (ADMA) are endogenous inhibitors of cellular L-arginine uptake and/or nitric oxide (NO) synthesis that are implicated in renal parenchymal and Dahl salt-sensitive hypertension. Since the L-arginine:(L-NMA+ADMA) ratio determines NO synthase (NOS) activity, we compared the immunohistochemical distribution of NOS with N G , N G -Dimethylarginine dimethylaminohydrolase (DDAH), which inactivates Dimethylarginines (DMA) and L-NMA by hydrolysis to L-citrulline. Neuronal NOS (nNOS) was expressed predominantly in tubular epithelial cells of macula densa (MD), endothelial NOS (eNOS) in vascular endothelial cells (EC), and inducible NOS (iNOS) quite widely in tubular epithelium, including proximal tubules (PT), thick ascending limbs of Henle (TAL), distal convoluted tubule and intercalated cells (IC) of the collecting duct. Immunostaining for DDAH was present in PT, TAL, MD, and IC, and was also present in the glomerulus, Bowman's capsule, and endothelium of blood vessels. DDAH was detected in small vesicles of TAL and PT by electron microscopic (EM) immunocytochemistry. To study the effects of methylarginines on tubuloglomerular feedback (TGF) response, vehicle or methylarginines (10 −3 M) were added to artificial tubular fluid (ATF) perfused orthogradely from the late PT at 40nl. min −1 while assessing changes in glomerular capillary pressure from proximal stop flow pressure (PSF). Whereas the maximal TGF responses were unchanged by vehicle (ΔTGF 0 ± 0%) or symmetric DMA (SDMA; +1 ± 2%, NS), they were enhanced by L-NMA (+22 ± 4%, P P −3 M) or vehicle were co-perfused orthogradely with [ 3 H]-L-arginine from the late PT and collected at the early distal tubule to study arginine uptake from the perfused loop of Henle. All methylarginines reduced fractional loop [ 3 H] absorption significantly ( P
