Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway

Weis, Michael; Kledal, Thomas N.; Lin, Ken Y.; Panchal, Shyam; Gao, Shao-Zhou; Valantine, Hannah A.; Mocarski, Edward S.; Cooke, John P.

doi:10.1161/01.cir.0000109692.16004.af

Cited by 134 publications

(47 citation statements)

References 45 publications

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“…In addition, DDAH activity is positively regulated by probucol (a potent antioxidant) (67), taurine (a semiessential amino acid with antioxidant properties) (174), insulin plus adiponectin (42), pravastatin (a cholesterol-lowering agent) (230), estradiol (59,112), IL-1␤ (191), and fenofibrate or pyrrolidine dithiocarbamate (an antagonist of nuclear factor-B) (228). DDAH activity is negatively regulated by CF6 (175), lipopolysaccharide (225), glycosylated bovine serum albumin (229), the erythropoietin analogs, epoetin-␤ and darbepoetin-␣ (146), high concentrations of glucose (160), oxLDL or TNF-␣ (64), cholesterol or homocysteine (167), and by cytomegalovirus infection (211). Almost all of these observations are performed in cultured endothelial cells or smooth muscle cells.…”

Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

286

301

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Palm F, Onozato ML, Luo Z, Wilcox CS. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293: H3227-H3245, 2007. First published October 12, 2007; doi:10.1152 doi:10. /ajpheart.00998.2007 )-dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS). ADMA is a risk factor for endothelial dysfunction, cardiovascular mortality, and progression of chronic kidney disease. Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) metabolize ADMA. DDAH-1 is the predominant isoform in the proximal tubules of the kidney and in the liver. These organs extract ADMA from the circulation. DDAH-2 is the predominant isoform in the vasculature, where it is found in endothelial cells adjacent to the cell membrane and in intracellular vesicles and in vascular smooth muscle cells among the myofibrils and the nuclear envelope. In vivo gene silencing of DDAH-1 in the rat and DDAH ϩ/Ϫ mice both have increased circulating ADMA, whereas gene silencing of DDAH-2 reduces vascular NO generation and endothelium-derived relaxation factor responses. DDAH-2 also is expressed in the kidney in the macula densa and distal nephron. Angiotensin type 1 receptor activation in kidneys reduces the expression of DDAH-1 but increases the expression of DDAH-2. This rapidly evolving evidence of isoform-specific distribution and regulation of DDAH expression in the kidney and blood vessels provides potential mechanisms for nephron site-specific regulation of NO production. In this review, the recent advances in the regulation and function of DDAH enzymes, their roles in the regulation of NO generation, and their possible contribution to endothelial dysfunction in patients with cardiovascular and kidney diseases are discussed. nitric oxide synthase; hypertension; diabetes mellitus; chronic kidney disease; asymmetric dimethylarginineis an endogenous methylated amino acid that inhibits the constitutive endothelial (e) or type III and neuronal (n) or type I isoforms of nitric oxide (NO) synthase (NOS) (49,91,103,199). It is a less potent inhibitor of the inducible (i) or type II NOS isoform (41,191,213). Proteins are subject to methylation of arginine residues by protein arginine methyltransferase (PRMT). S-adenosylmethionine, which is synthesized from methionine and ATP, serves as the methyl donor and, in the process, is converted to S-adenosylhomocysteine, which itself can be hydrolyzed to homocysteine. Remethylation of homocysteine in the "remethylation pathway" regenerates methionine (14,179). ADMA is released by protein hydrolysis and exported from the cell and taken up by other cells via system y ϩ carriers of the cationic amino acid (CAT) family (14,196,212). ADMA is eliminated both by renal excretion and metabolic degradation. Its metabolism is facilitated by dimethylarginine dimethylaminohydrolases (DDAHs), which are expressed as type 1 and 2 isoforms. Recent studies have shown differential sites of expression of DDAH-1 and -2 in blo...

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Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

286

301

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“…15 Cardiotropic viruses may also influence diastolic function via cytokine-dependent pathomechanisms, leading to an impairment of the intracellular calcium cycle by inducing changes in the extracellular matrix composition or by impairment of the nitric oxide synthase pathway, resulting in endothelial dysfunction. 16,17 …”

Section: Cardiotropic Viral Infection and Their Clinical Manifestationsmentioning

confidence: 99%

High Prevalence of Cardiac Parvovirus B19 Infection in Patients With Isolated Left Ventricular Diastolic Dysfunction

et al. 2005

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Background-The etiology of left ventricular (LV) isolated diastolic dysfunction often remains unclear. In the present study, we report a strong association between parvovirus B19 (PVB19) genomes and isolated LV diastolic dysfunction. Methods and Results-In 70 patients (meanϮSD age, 43Ϯ11 years) admitted with exertional dyspnea and/or reduced exercise tolerance despite preserved LV systolic contractility (ejection fractionϭ68%), isolated diastolic dysfunction was clinically suspected. Patients with classic risk factors for diastolic dysfunction such as hypertension, coronary heart disease, diabetes mellitus, or pulmonary disease had been excluded. Diastolic function was assessed by echocardiography and LV and RV catheterization. Endomyocardial biopsies (EMBs) were analyzed for the presence of storage or infiltrative diseases or myocarditis, including molecular screening for cardiotropic virus genomes. In a substudy of 24 patients who reported atypical angina, coronary endothelial function was additionally investigated with a coronary Doppler flow-wire technique. In 37 of 70 patients (53%), isolated diastolic dysfunction was confirmed as the cause of their clinical symptoms. No evidence for cardiac storage or infiltrative diseases was found in these cases, but in 35 of 37 of these patients (95%), cardiotropic virus genomes were detected in EMBs (PϽ0.001). PVB19 was the most frequent pathogen in 31 of 37 patients (84%). In a subgroup of 10 patients with diastolic dysfunction and coexisting endothelial dysfunction, all 10 (100%) were PVB19 positive. Conclusions-PVB19 genomes were predominant in patients with unexplained, isolated diastolic dysfunction. A strong association with the incidence of endothelial dysfunction was obvious, consistent with the hypothesis that PVB19-induced endothelial dysfunction may be a possible pathomechanism underlying diastolic dysfunction.

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“…More specifically, oxidative stress, which is strongly present in manifestations of ESRD, my affect DDAH activity by modification of a critical cysteine residue in the enzyme's active site [31]. Also, reduced DDAH activity might be due to an effect of different stimuli such as inflammatory cytokines, hyperhomocystinemia, hyperglycemia, and infectious agents [32][33][34][35].…”

Section: Discussionmentioning

confidence: 99%

ADMA and C-reactive protein as mortality predictors in dialysis patients

Ignjatović¹,

Cvetković²,

Pavlović

et al. 2013

Open Medicine

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AbstractThere is a higher mortality between patients with end-stage renal disease than patients in the general population. These circumstances have led to a search for risk factors as predictors of mortality in dialysis patients. Amongst those, inhibitors of the nitric-oxide (NO) synthesis deserve special attention, since patients with end-stage renal disease are also characterized by accelerated atherosclerosis. Asymmetric-dimethylarginine (ADMA) and symmetric-dimethylarginine (SDMA), as well as C-reactive protein (CRP), have also been recognized as predictors of mortality in patients on dialysis. The aim of our study was to compare the prediction power of ADMA, SDMA and CRP for all-cause mortality in patients with end stage renal disease during the fourteen month follow-up. In total 162 patients on hemodialysis were included. ADMA and SDMA were measured by the high-performance liquid chromatography (HPLC); CRP was measured using immunonephelometric assays. During the 14-month period 28 patients (34.1%) died from all-cause mortality. Using univariate analysis, hazard ratios (HR) of the potential independent predictors of mortality in hemodialysis patients were ADMA (HR 1.39 (1.01–1.91) p=0.043) and CRP (HR 1.024 (1.009–1.1.040) p=0.001). Further, multivariate analysis (MVA), however, showed that ADMA is the only predictor of all-cause mortality (HR 1.76 (1.002–3.11) P=0.049), while SDMA failed to predict death in this population. Therefore, our data shows that ADMA is an independent and better marker of all-cause mortality compared with CRP.

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Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway

Cited by 134 publications

References 45 publications

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

High Prevalence of Cardiac Parvovirus B19 Infection in Patients With Isolated Left Ventricular Diastolic Dysfunction

ADMA and C-reactive protein as mortality predictors in dialysis patients

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