Low-Circulating Homoarginine is Associated with Dilatation and Decreased Function of the Left Ventricle in the General Population

Low homoarginine is an independent marker of mortality in heart failure patients and incident cardiovascular events. Whether homoarginine is related with healthier cardiac structure and function is currently unclear. We used data of the population-based Study of Health in Pomerania (SHIP-Trend) to assess this relation. Homoarginine was measured in serum using liquid chromatography-tandem mass spectrometry. Linear regression models assessed the relation between homoarginine and several structural as well as functional parameters and N-terminal pro B-type natriuretic peptide (NTproBNP). All models were adjusted for age, sex, body mass index, and renal function. A total of 3113 subjects (median age 48 (25th percentile 37 to 75th percentile 60) years, 46% male) were included. A standard deviation decrease in homoarginine was associated with a larger left ventricular diastolic diameter (0.3;95%-confidence interval (CI): 0.2 to 0.5 mm;p < 0.001), left ventricular systolic diameter (0.38;95%-CI: -0.22 to 0.54 mm;p < 0.001) as well as a less relative wall thickness (-0.003 95%-CI: -0.006 to -0.0008;p = 0.01), left ventricular ejection fraction (-0.47;95%-CI: -0.79 to -0.15%;p < 0.01) and fractional shortening (-0.35;95%-CI: -0.62 to 0.07%;p = 0.01). Low homoarginine was also related to higher NTproBNP (-0.02 95%-CI: -0.034 to -0.009 log pg/mL;p < 0.01). Lower serum homoarginine is associated with dilatation of the heart and decreased function. Prospective clinical studies should assess if homoarginine supplementation improves cardiac health in subjects with low serum concentrations

Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the CommunityThe Gutenberg Health Study

Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive biomarker remains unknown. We measured plasma levels of homoarginine in the population-based Gutenberg health study (3761 patients included, of them 51.7% males), mean age 55.6 +/- 10.9 years-old. Associations between homoarginine and intermediate electrocardiographic and echocardiographic phenotypes and manifest AF were examined. Patients with AF (124 patients, of them 73.4% males) had a mean age 64.8 +/- 8.6 years-old compared to a mean age of 55.3 +/- 10.9 in the population without AF (p-value < 0.001) and showed a less beneficial risk factor profile. The median homoarginine levels in individuals with and without AF were 1.9 mol/L (interquartile range (IQR) 1.5-2.5) and 2.0 mol/L (IQR 1.5-2.5), respectively, p = 0.56. In multivariable-adjusted regression analyses homoarginine was not statistically significantly related to electrocardiographic variables. Among echocardiographic variables beta per standard deviation increase was -0.12 (95% confidence interval (CI) -0.23-(-0.02);p = 0.024) for left atrial area and -0.01 (95% CI -0.02-(-0.003);p = 0.013) for E/A ratio. The odds ratio between homoarginine and AF was 0.91 (95% CI 0.70-1.16;p = 0.45). In our large, population-based cross-sectional study, we did not find statistically significant correlations between lower homoarginine levels and occurrence or persistence of AF or most standard electrocardiographic phenotypes, but some moderate inverse associations with echocardiographic left atrial size and E/A. Homoarginine may not represent a strong biomarker to identify individuals at increased risk for AF. Further investigations will be needed to elucidate the role of homoarginine and cardiac function

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

HapMap imputed genome-wide association studies (GWAS) have revealed &gt;50 loci at which common variants with minor allele frequency &gt;5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value &lt; 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR &lt; 0.05) genes and 127 significantly (FDR &lt; 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples

Mechanisms of Disease: L-arginine in coronary atherosclerosis - a clinical perspective

L-Arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide in the vascular endothelium, thus its effects are mediated largely by increases in nitric oxide production. L-Arginine has antioxidant and antiapoptotic properties, increases smooth muscle relaxation, inhibits the expression of adhesion molecules and chemotactic peptides, decreases endothelin-1 expression, and inhibits platelet aggregation. This amino acid also improves endothelial function in patients with coronary artery disease and dilates human epicardial atheromatous coronary arteries. Despite the positive results from small case - control studies, it is still unclear whether chronic administration of L-arginine has any effect on clinical outcome in patients with coronary artery disease. In addition, other indirect strategies, such as the inhibition of arginase, could prove more effective at improving intracellular L-arginine bioavailability than exogenous L-arginine administration. The potential clinical usefulness of L-arginine, therefore, needs further evaluation in large, prospective clinical trials. Here, we present a critique of the existing literature about the role of L-arginine in the prevention of atherosclerosis

Homoarginine supplementation improves blood glucose in diet-induced obese mice

l-Homoarginine (hArg) is an endogenous amino acid which has emerged as a novel biomarker for stroke and cardiovascular disease. Low circulating hArg levels are associated with increased mortality and vascular events, whereas recent data have revealed positive correlations between circulating hArg and metabolic vascular risk factors like obesity or blood glucose levels. However, it is unclear whether hArg levels are causally linked to metabolic parameters. Therefore, the aim of our study was to investigate whether hArg directly influences body weight, blood glucose, glucose tolerance or insulin sensitivity. Here, we show that hArg supplementation (14 and 28 mg/mL orally per drinking water) ameliorates blood glucose levels in mice on high-fat diet (HFD) by a reduction of 7.3 +/- A 3.7 or 13.4 +/- A 3.8 %, respectively. Fasting insulin concentrations were slightly, yet significantly affected (63.8 +/- A 11.3 or 162.1 +/- A 39.5 % of control animals, respectively), whereas body weight and glucose tolerance were unaltered. The substantial augmentation of hArg plasma concentrations in supplemented animals (327.5 +/- A 40.4 or 627.5 +/- A 60.3 % of control animals, respectively) diminished profoundly after the animals became obese (129.9 +/- A 16.6 % in control animals after HFD vs. 140.1 +/- A 8.5 or 206.3 +/- A 13.6 %, respectively). This hArg-lowering effect may contribute to the discrepancy between the inverse correlation of plasma hArg levels with stroke and cardiovascular outcome, on the one hand, and the direct correlation with cardiovascular risk factors like obesity and blood glucose, on the other hand, that has been observed in human studies. Our results suggest that the glucose-lowering effects of hArg may reflect a compensatory mechanism of blood glucose reduction by hArg upregulation in obese individuals, without directly influencing body weight or glucose tolerance

Effects of acute and chronic stress on the L-arginine nitric oxide pathway in black and white South Africans: the sympathetic activity and ambulatory blood pressure in Africans study

OBJECTIVE: This study investigated the impact of stress on effectors of the L-arginine/nitric oxide (NO) system including the endogenous inhibitor asymmetric dimethylarginine (ADMA). METHODS: Black (n = 168) and white (n = 206) South African teachers were exposed to a mental and a physical stressor for 1 minute, respectively. Serum samples for determination of l-arginine, NO metabolites, ADMA, and symmetric dimethylarginine (SDMA) were obtained at rest and during stress exposure. Perception of task stressfulness was assessed on a 7-point Likert scale, and psychological distress was estimated by the General Health Questionnaire. RESULTS: Black South Africans exhibited higher resting levels of NO metabolites (adjusted mean [standard error of the mean] = 11.3 [1.3] versus 3.9 [1.1] μmol/l, p < .001) but lower circulating ADMA (0.62 [0.02] versus 0.70 [0.02] μmol/l, p = .004) and SDMA (0.41 [0.01] versus 0.53 [0.01] μmol/l, p < .001) than did white South Africans. Ethnicity-by-psychological distress interaction was observed for resting levels of ADMA (p = .002), SDMA (p = .038), and L-arginine (p = .048). Ethnic differences in responses to experimental stress were evident for NO metabolites (blacks versus whites: 5.94 [1.55] versus -0.74 [1.25] μmol/l, p = .004) and SDMA (blacks versus whites: -0.02 [0.01] versus 0.02 [0.01] μmol/l, p = .004). Ethnicity-by-psychological distress interaction for stress responses was found for l-arginine/ADMA ratio (p = .027). CONCLUSIONS: The l-arginine/NO system is affected by psychosocial distress with higher susceptibility in black South Africans. This interaction may contribute to the higher cardiovascular disease risk in black South African

Muscle phenotype of AGAT- and GAMT-deficient mice after simvastatin exposure

Statin-induced myopathy affects more than 10 million people worldwide. But discontinuation of statin treatment increases mortality and cardiovascular events. Recently, l-arginine:glycine amidinotransferase (AGAT) gene was associated with statin-induced myopathy in two populations, but the causal link is still unclear. AGAT is responsible for the synthesis of l-homoarginine (hArg) and guanidinoacetate (GAA). GAA is further methylated to creatine (Cr) by guanidinoacetate methyltransferase (GAMT). In cerebrovascular patients treated with statin, lower hArg and GAA plasma concentrations were found than in non-statin patients, indicating suppressed AGAT expression and/or activity (n = 272, P = 0.033 and P = 0.039, respectively). This observation suggests that statin-induced myopathy may be associated with AGAT expression and/or activity in muscle cells. To address this, we studied simvastatin-induced myopathy in AGAT- and GAMT-deficient mice. We found that simvastatin induced muscle damage and reduced AGAT expression in wildtype mice (myocyte diameter: 34.1 +/- 1.3 mu m vs 21.5 +/- 1.3 mu m, P = 0.026; AGAT expression: 1.0 +/- 0.3 vs 0.48 +/- 0.05, P = 0.017). Increasing AGAT expression levels of transgenic mouse models resulted in rising plasma levels of hArg and GAA (P < 0.01 and P < 0.001, respectively). Simvastatin-induced motor impairment was exacerbated in AGAT-deficient mice compared with AGAT-overexpressing GAMT(-/-) mice and therefore revealed an effect independent of Cr. But Cr supplementation itself improved muscle strength independent of AGAT expression (normalized grip strength: 55.8 +/- 2.9% vs 72.5% +/- 3.0%, P < 0.01). Homoarginine supplementation did not affect statin-induced myopathy in AGAT-deficient mice. Our results from clinical and animal studies suggest that AGAT expression/activity and its product Cr influence statin-induced myopathy independent of each other. The interplay between simvastatin treatment, AGAT expression and activity, and Cr seems to be complex. Further clinical pharmacological studies are needed to elucidate the underlying mechanism(s) and to evaluate whether supplementation with Cr, or possibly GAA, in patients under statin medication may reduce the risk of muscular side effects

Compositional and structural analysis of selected chromosomal domains from Saccharomyces cerevisiae

Chromatin is the template for replication and tran- scription in the eukaryotic nucleus, which needs to be defined in composition and structure before these processes can be fully understood. We report an isolation protocol for the targeted purifi- cation of specific genomic regions in their native chromatin context from Saccharomyces cerevisiae . Subdomains of the multicopy ribosomal DNA locus containing transcription units of RNA polymerases I, II or III or an autonomous replication sequence were independently purified in sufficient amounts and purity to analyze protein composition and histone modifications by mass spectrometry. We present and discuss the proteomic data sets obtained for chromatin in different functional states. The native chromatin was further amenable to electron mi- croscopy analysis yielding information about nucleosome occupancy and positioning at the single-molecule level. We also provide evidence that chromatin from virtually every single copy genomic locus of interest can be purified and analyzed by this technique