Publications by authors named "Roman N Rodionov"

46 Publications

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

Mol Psychiatry 2021 Jun 17. Epub 2021 Jun 17.

Zentrums für Apherese- und Hämofiltration am INUS Tagesklinikum, Cham, Germany.

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-021-01148-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209771PMC
June 2021

Viral infiltration of pancreatic islets in patients with COVID-19.

Nat Commun 2021 06 10;12(1):3534. Epub 2021 Jun 10.

Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23886-3DOI Listing
June 2021

Divergent Dimethylarginine Dimethylaminohydrolase Isoenzyme Expression in the Central Nervous System.

Cell Mol Neurobiol 2021 May 20. Epub 2021 May 20.

Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

The endogenous methylated derivative of ʟ-arginine, N,N-dimethyl-ʟ-arginine (asymmetric dimethylarginine, ADMA), an independent risk factor in many diseases, inhibits the activity of nitric oxide synthases and, consequently, modulates the availability of nitric oxide. While most studies on the biological role of ADMA have focused on endothelial and inducible nitric oxide synthases modulation and its contribution to cardiovascular, metabolic, and renal diseases, a role in regulating neuronal nitric oxide synthases and pathologies of the central nervous system is less understood. The two isoforms of dimethylarginine dimethylaminohydrolase (DDAH), DDAH1 and DDAH2, are thought to be the main enzymes responsible for ADMA catabolism. A current impediment is limited knowledge on specific tissue and cellular distribution of DDAH enzymes within the brain. In this study, we provide a detailed characterization of the regional and cellular distribution of DDAH1 and DDAH2 proteins in the adult murine and human brain. Immunohistochemical analysis showed a wide distribution of DDAH1, mapping to multiple cell types, while DDAH2 was detected in a limited number of brain regions and exclusively in neurons. Our results provide key information for the investigation of the pathophysiological roles of the ADMA/DDAH system in neuropsychiatric diseases and pave the way for the development of novel selective therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10571-021-01101-7DOI Listing
May 2021

Homoarginine and methylarginines independently predict long-term outcome in patients presenting with suspicion of venous thromboembolism.

Sci Rep 2021 May 5;11(1):9569. Epub 2021 May 5.

Department of Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.

Endogenous arginine derivatives homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethyarginine (SDMA) are independent mortality predictors in atherosclerotic cardiovascular disease (CVD). Our study reports the first analysis, whether homoarginine, ADMA and SDMA predict venous thromboembolism (VTE) recurrence and overall mortality in patients with suspected acute VTE. We assessed serum levels of homoarginine, ADMA and SDMA by LC-MS/MS in 865 individuals from a prospective consecutive cohort of patients with clinical suspicion of VTE. The median follow-up time for mortality was 1196 days. VTE was confirmed by imaging in 418 patients and excluded in 447 patients. Low levels of homoarginine and high levels of ADMA or SDMA independently predicted all-cause mortality after adjustment for sex, age, oral anticoagulants, body mass index, arterial hypertension, diabetes mellitus, smoking, dyslipidemia, chronic heart failure, history of stroke, creatinine and cancer both in patients with VTE and without VTE. Interestingly, none of those parameters was predictive for VTE recurrence. We provide the first report that low circulating levels of homoarginine and high circulating levels of ADMA and SDMA independently predict all-cause mortality in patients with suspected VTE. These parameters might serve as markers of "frailty" and should be considered for future risk stratification approaches in this clinical population. Taking into account that homoarginine supplementation is protective in animal models of CVD and safe in healthy human volunteers, our study provides the basis for future homoarginine supplementation studies in patients with suspected VTE to investigate possible direct protective effects of homoarginine in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-88986-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100302PMC
May 2021

Phosphodiesterase-5 Inhibitors and Survival in Men With Coronary Artery Disease.

J Am Coll Cardiol 2021 Mar;77(12):1551-1553

Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, Dresden, Germany; College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2021.02.021DOI Listing
March 2021

Scarred Lung. An Update on Radiation-Induced Pulmonary Fibrosis.

Front Med (Lausanne) 2020 15;7:585756. Epub 2021 Jan 15.

Department of Anesthesiology and Critical Care Medicine, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany.

Radiation-induced pulmonary fibrosis is a common severe long-time complication of radiation therapy for tumors of the thorax. Current therapeutic options used in the clinic include only supportive managements strategies, such as anti-inflammatory treatment using steroids, their efficacy, however, is far from being satisfactory. Recent studies have demonstrated that the development of lung fibrosis is a dynamic and complex process, involving the release of reactive oxygen species, activation of Toll-like receptors, recruitment of inflammatory cells, excessive production of nitric oxide and production of collagen by activated myofibroblasts. In this review we summarized the current state of knowledge on the pathophysiological processes leading to the development of lung fibrosis and we also discussed the possible treatment options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2020.585756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843914PMC
January 2021

Transport of L-Arginine Related Cardiovascular Risk Markers.

J Clin Med 2020 Dec 8;9(12). Epub 2020 Dec 8.

Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91504 Erlangen, Germany.

L-arginine and its derivatives, asymmetric and symmetric dimethylarginine (ADMA and SDMA) and L-homoarginine, have emerged as cardiovascular biomarkers linked to cardiovascular outcomes and various metabolic and functional pathways such as NO-mediated endothelial function. Cellular uptake and efflux of L-arginine and its derivatives are facilitated by transport proteins. In this respect the cationic amino acid transporters CAT1 and CAT2 ( and ) and the system yL amino acid transporters ( and ) have been most extensively investigated, so far, but the number of transporters shown to mediate the transport of L-arginine and its derivatives is constantly increasing. In the present review we assess the growing body of evidence regarding the function, expression, and clinical relevance of these transporters and their possible relation to cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9123975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764698PMC
December 2020

Comparison of potency assays to assess SARS-CoV-2 neutralizing antibody capacity in COVID-19 convalescent plasma.

J Virol Methods 2021 02 1;288:114031. Epub 2020 Dec 1.

Paul-Ehrlich-Institut, Department of Virology, Paul-Ehrlich Strasse 51-59, 63225 Langen, Germany. Electronic address:

Convalescent plasma is plasma collected from individuals after resolution of an infection and the development of antibodies. Passive antibody administration by transfusion of convalescent plasma is currently in clinical evaluations to treat COVID-19 patients. The level of neutralizing antibodies vary among convalescent patients and fast and simple methods to identify suitable plasma donations are needed. We compared three methods to determine the SARS-CoV-2 neutralizing activity of human convalescent plasma: life virus neutralization by plaque reduction assay, a lentiviral vector based pseudotype neutralization assay and a competition ELISA-based surrogate virus neutralization assay (sVNT). Neutralization activity correlated among the different assays; however the sVNT assay was overvaluing the low neutralizing plasma. On the other hand, the sVNT assay required the lowest biosafety level, is fast and is sufficient to identify highly neutralizing plasma samples. Though weakly neutralizing samples were more reliable detected by the more challenging lentiviral vector based assays or virus neutralization assays. Spike receptor binding competition assays are suitable to identify highly neutralizing plasma samples under low biosafety requirements. Detailed analysis of in vitro neutralization activity requires more sophisticated methods that have to be performed under higher biosafety levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jviromet.2020.114031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707675PMC
February 2021

The role of alanine glyoxylate transaminase-2 (agxt2) in β-alanine and carnosine metabolism of healthy mice and humans.

Eur J Appl Physiol 2020 Dec 18;120(12):2749-2759. Epub 2020 Sep 18.

Department of Movement and Sports Sciences, Ghent University, Watersportlaan 2, 9000, Gent, Belgium.

Purpose: Chronic β-alanine supplementation leads to increased levels of muscle histidine-containing dipeptides. However, the majority of ingested β-alanine is, most likely, degraded by two transaminases: GABA-T and AGXT2. In contrast to GABA-T, the in vivo role of AGXT2 with respect to β-alanine metabolism is unknown. The purpose of the present work is to investigate if AGXT2 is functionally involved in β-alanine homeostasis.

Methods: Muscle histidine-containing dipeptides levels were determined in AGXT2 overexpressing or knock-out mice and in human subjects with different rs37369 genotypes which is known to affect AGXT2 activity. Further, plasma β-alanine kinetic was measured and urine was obtained from subjects with different rs37369 genotypes following ingestion of 1400 mg β-alanine.

Result: Overexpression of AGXT2 decreased circulating and muscle histidine-containing dipeptides (> 70% decrease; p < 0.05), while AGXT2 KO did not result in altered histidine-containing dipeptides levels. In both models, β-alanine remained unaffected in the circulation and in muscle (p > 0.05). In humans, the results support the evidence that decreased AGXT2 activity is not associated with altered histidine-containing dipeptides levels (p > 0.05). Additionally, following an acute dose of β-alanine, no differences in pharmacokinetic response were measured between subjects with different rs37369 genotypes (p > 0.05). Interestingly, urinary β-alanine excretion was 103% higher in subjects associated with lower AGXT2 activity, compared to subjects associated with normal AGXT2 activity (p < 0.05).

Conclusion: The data suggest that in vivo, β-alanine is a substrate of AGXT2; however, its importance in the metabolism of β-alanine and histidine-containing dipeptides seems small.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00421-020-04501-7DOI Listing
December 2020

Nutritional and metabolic regulation of the metabolite dimethylguanidino valeric acid: an early marker of cardiometabolic disease.

Am J Physiol Endocrinol Metab 2020 09 14;319(3):E509-E518. Epub 2020 Jul 14.

Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.

Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpendo.00207.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509244PMC
September 2020

Inflammatory Cell Infiltration of Adrenals in COVID-19.

Horm Metab Res 2020 Sep 6;52(9):639-641. Epub 2020 Jul 6.

Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originated in November-December 2019 in Wuhan, China, and has rapidly spread around the world causing severe health and socioeconomical damage to the entire civilization. The key feature of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is upper respiratory tract infection, which may be complicated by bilateral pneumonia. Angiotensin converting enzyme 2 (ACE2) has been identified as a key host factor, required for virus entry into cells. Interestingly, ACE2 is expressed not only in the respiratory system, but also in the other organs and systems including adrenal glands. Here we provide the first description of the pathomorphological changes in adrenal glands in patients with severe COVID-19 characterized by perivascular infiltration of CD3+ and CD8+ T-lymphocytes. Due to the central role of the adrenals in the stress response of the organism, this finding is of potential clinical relevance, because infection with the SARS-CoV-2 virus might critically impair adrenal function under pathophysiological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1191-8094DOI Listing
September 2020

Is There a Role for Environmental and Metabolic Factors Predisposing to Severe COVID-19?

Horm Metab Res 2020 Jul 29;52(7):540-546. Epub 2020 Jun 29.

Zentrum für Apherese- und Hämofiltration am INUS Tagesklinikum-Cham, Cham, Germany.

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic affects people around the world. However, there have been striking differences in the number of infected individuals and deaths in different countries. Particularly, within Central Europe in countries that are similar in ethnicity, age, and medical standards and have performed similar steps of containment, such differences in mortality rates remain inexplicable. We suggest to consider and explore environmental factors to explain these intriguing variations. Countries like Northern Italy, France, Spain, and UK have suffered from 5 times more deaths from the corona virus infection than neighboring countries like Germany, Switzerland, Austria, and Denmark related to the size of their respective populations. There is a striking correlation between the level of environmental pollutants including pesticides, dioxins, and air pollution such as NO known to affect immune function and healthy metabolism with the rate of mortality in COVID-19 pandemic in these European countries. There is also a correlation with the use of chlorination of drinking water in these regions. In addition to the improvement of environmental protective programs, there are possibilities to lower the blood levels of these pollutants by therapeutic apheresis. Furthermore, therapeutic apheresis might be an effective method to improve metabolic inflammation, altered vascular perfusion, and neurodegeneration observed as long-term complications of COVID-19 disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1182-2016DOI Listing
July 2020

Cardio-Metabolic Effects of High-Fat Diets and Their Underlying Mechanisms-A Narrative Review.

Nutrients 2020 May 21;12(5). Epub 2020 May 21.

Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.

The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models-the diacylglycerol (DAG) model and the ceramide model-have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12051505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284903PMC
May 2020

The ACE-2 in COVID-19: Foe or Friend?

Horm Metab Res 2020 May 27;52(5):257-263. Epub 2020 Apr 27.

Tan Tock Seng Hospital, Singapore.

COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-ATR axis and ACE-2-Ang-(1-7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-ATR axis with a downregulation of ACE-2-Ang-(1-7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1-7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1-7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1155-0501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339082PMC
May 2020

Inhibition of Dimethylarginine Dimethylaminohydrolase (DDAH) Enzymes as an Emerging Therapeutic Strategy to Target Angiogenesis and Vasculogenic Mimicry in Cancer.

Front Oncol 2019 9;9:1455. Epub 2020 Jan 9.

Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

The small free radical gas nitric oxide (NO) plays a key role in various physiological and pathological processes through enhancement of endothelial cell survival and proliferation. In particular, NO has emerged as a molecule of interest in carcinogenesis and tumor progression due to its crucial role in various cancer-related events including cell invasion, metastasis, and angiogenesis. The dimethylarginine dimethylaminohydrolase (DDAH) family of enzymes metabolize the endogenous nitric oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA), and are thus key for maintaining homeostatic control of NO. Dysregulation of the DDAH/ADMA/NO pathway resulting in increased local NO availability often promotes tumor growth, angiogenesis, and vasculogenic mimicry. Recent literature has demonstrated increased DDAH expression in tumors of different origins and has also suggested a potential ADMA-independent role for DDAH enzymes in addition to their well-studied ADMA-mediated influence on NO. Inhibition of DDAH expression and/or activity in cell culture models and studies has indicated the potential therapeutic benefit of this pathway through inhibition of both angiogenesis and vasculogenic mimicry, and strategies for manipulating DDAH function in cancer are currently being actively pursued by several research groups. This review will thus provide a timely discussion on the expression, regulation, and function of DDAH enzymes in regard to angiogenesis and vasculogenic mimicry, and will offer insight into the therapeutic potential of DDAH inhibition in cancer based on preclinical studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962312PMC
January 2020

Kidney and liver are the main organs of expression of a key metabolic enzyme alanine:glyoxylate aminotransferase 2 in humans.

Atheroscler Suppl 2019 Dec;40:106-112

University Center for Vascular Medicine & Department of Medicine III - Section Angiology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Electronic address:

Background: The metabolic syndrome is a cluster of cardiovascular risk factors and is highly predictive for development of cardiovascular diseases. An association between elevated plasma levels of the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) and risk of cardiovascular diseases has been demonstrated in numerous epidemiological studies. ADMA can be catabolized by dimethylarginine dimethylaminohydrolase (DDAH) or metabolized through a much less understood alternative pathway by alanine:glyoxylate aminotransferase 2 (AGXT2) with the formation of α-keto-δ-(N,N-dimethylguanidino)valeric acid (ADGV). Previous RT-PCR and Western Blot studies suggested that Agxt2 is expressed in the mouse kidney and liver at comparable levels, while Northern Blot and in-situ RNA-hybridisation experiments demonstrated that the kidney is the main organ of Agxt2 expression in rats. Given this discrepancy, the goal of the current study was to analyse the expression of AGXT2 in human tissues.

Material And Methods: We analyzed AGXT2 expression in human tissues from a normal tissue bank by RT-PCR and further validated the results by Western Blot. We also performed immunohistochemical staining for AGXT2 and double fluorescent staining with an anti-AGXT2 antibody and a monoclonal anti-mitochondrial antibody.

Results: We saw the strongest expression of AGXT2 in the kidney and liver and confirmed this results on protein level. By IHC staining we were able to show that AGXT2 is present in the convoluted tubule in the kidney and in the liver hepatocytes. The double fluorescent staining revealed mitochondrial localization of AGXT2.

Conclusions: Our current data suggest that both hepatocytes and kidney tubular epithelial cells are the major sources of AGXT2 in humans. We also demonstrated the mitochondrial localization of human AGXT2 enzyme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosissup.2019.08.041DOI Listing
December 2019

ADMA elevation does not exacerbate development of diabetic nephropathy in mice with streptozotocin-induced diabetes mellitus.

Atheroscler Suppl 2019 Dec;40:100-105

Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.

Background And Aims: Cardiovascular disease is nowadays the major cause of mortality and morbidity worldwide. The risk of developing cardiovascular disease is significantly increased in patients with diabetic nephropathy. It has been suggested that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthases (NOS), may play an important role in the pathogenesis of diabetic nephropathy. ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase 1 (DDAH1). The goal of this study was to test the hypothesis that elevation of systemic ADMA levels by knocking out DDAH1 would exacerbate functional and structural glomerular abnormalities in a murine model of diabetic nephropathy.

Methods: Streptozotocin (STZ) was used to induce diabetes in adult DDAH1 knock-out and wild type mice. Healthy mice served as controls. Mice were sacrificed after 20 weeks of diabetes. Plasma ADMA levels were assessed by isotope-dilution tandem mass spectrometry and albumin by ELISA. Kidneys were used for FACS analysis and were also stained for markers of inflammation, cell proliferation, glomerular cells and cell matrix.

Results: STZ led to development of diabetes mellitus in all injected animals. Deficiency of DDAH1 led to a significant increase in plasma ADMA levels in healthy and diabetic mice. The diabetic state itself did not influence systemic ADMA levels. Diabetic mice of both genotypes developed albuminuria and had increased glomerulosclerosis index. There were no changes in desmin expression, glomerular cell proliferation rate, matrix expansion and expression of Mac-2 antigen in the diabetic mice of both genotypes as compared to the healthy ones.

Conclusions: In summary, STZ-induced diabetes led to the development of early features of diabetic nephropathy. Deficiency of DDAH1 and subsequent increase in systemic ADMA levels did not exacerbate these changes, indicating that ADMA is not the major mediator of diabetic nephropathy in this experiment model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosissup.2019.08.040DOI Listing
December 2019

The Second Life of Methylarginines as Cardiovascular Targets.

Int J Mol Sci 2019 Sep 17;20(18). Epub 2019 Sep 17.

Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, Technische Universität Dresden, 01307 Dresden, Germany.

Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20184592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769906PMC
September 2019

Are Lifestyle Therapies Effective for NAFLD Treatment?

Trends Endocrinol Metab 2019 10 15;30(10):701-709. Epub 2019 Aug 15.

Institute for Clinical Diabetology and Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany.

Nonalcoholic fatty liver disease (NAFLD) is becoming the most common liver disorder worldwide. Specifically, nonalcoholic steatohepatitis (NASH) and fibrosis pose an enormous burden for patients and health-care systems. In the absence of approved pharmacological therapies, effective lifestyle interventions for NAFLD, such as dietary strategies and exercise training, are currently the therapeutic strategies of choice. This review covers the influence of macronutrient quality and quantity (i.e., low-carbohydrate and high-protein diets), for successful reduction of intrahepatocellular lipids (IHL). Moreover, we discuss the effectiveness of different modalities of physical exercising with and without weight loss. These lifestyle modifications not only provide strategies to reduce IHL but may also hold a still underestimated potential to induce improvement and/or even remission of NAFLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tem.2019.07.013DOI Listing
October 2019

Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease.

J Am Heart Assoc 2019 07 15;8(14):e012486. Epub 2019 Jul 15.

2 Department of Biomedical Sciences New York Institute of Technology College of Osteopathic Medicine Old Westbury NY.

Background Homoarginine ( hA rg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hA rg can inhibit tissue-nonspecific alkaline phosphatase ( TNAP ), an enzyme that promotes vascular calcification. We hypothesized that hA rg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results TNAP was overexpressed in the endothelium in mice homozygous for a low-density lipoprotein receptor mutation (wicked high cholesterol [ WHC ] allele). WHC and WHC -endothelial TNAP mice received placebo or hA rg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC -endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P<0.0001), increased coronary calcium and lipids ( P<0.01), increased left ventricular end-diastolic diameter ( P<0.0001), reduced ejection fraction ( P<0.05), and increased myocardial fibrosis ( P<0.0001) compared with WHC mice. Contrary to our hypothesis, hA rg neither inhibited TNAP activity in vivo nor reduced coronary artery calcification and atherosclerosis in WHC -endothelial TNAP mice; however, compared with the placebo, hA rg prevented left ventricular dilatation ( P<0.01), preserved ejection fraction ( P<0.05), and reduced myocardial fibrosis ( P<0.001). Conclusions The beneficial effect of hA rg supplementation in the setting of calcified coronary artery disease is likely due to its direct protective actions on the myocardial response to the ischemic injury and not to the inhibition of TNAP activity and calcification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.012486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662144PMC
July 2019

New horizons in arginine metabolism, ageing and chronic disease states.

Age Ageing 2019 11;48(6):776-782

Department of Biomedical Sciences, University of Sassari, Sassari, Italy.

The elucidation of the metabolic pathways of the amino acid arginine and their role in health and disease have been an intensive focus of basic and clinical research for over a century. The recent advent of robust analytical techniques for biomarker assessment in large population cohorts has allowed the investigation of the pathophysiological role of specific arginine metabolites in key chronic disease states in old age, particularly those characterised by a reduced synthesis of endothelial nitric oxide, with consequent vascular disease and atherosclerosis. Two arginine metabolites have been increasingly studied in regard to their potential role in risk stratification and in the identification of novel therapeutic targets: the methylated arginine asymmetric dimethylarginine (ADMA) and the arginine analogue homoarginine. Higher circulating concentrations of ADMA, a potent inhibitor of nitric oxide synthesis, have been shown to predict adverse cardiovascular outcomes. By contrast, there is emerging evidence that homoarginine might exert cardioprotective effects. This review highlights recent advances in the biological and clinical role of ADMA and homoarginine in cardiovascular disease and other emerging fields, particularly chronic obstructive pulmonary disease, dementia, and depression. It also discusses opportunities for future research directions with the ultimate goal of translating knowledge of arginine metabolism, and its role in health and disease, into the clinical care of older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ageing/afz083DOI Listing
November 2019

Is Homoarginine a Protective Cardiovascular Risk Factor?

Arterioscler Thromb Vasc Biol 2019 05;39(5):869-875

Division of Angiology, Department of Internal Medicine III, University Center for Vascular Medicine, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Germany (N.J., N.W., R.N.R.).

A series of recent epidemiological studies have implicated the endogenous nonproteinogenic amino acid l-homoarginine as a novel candidate cardiovascular risk factor. The association between homoarginine levels and the risk of adverse cardiovascular outcomes is inverse (ie, high cardiovascular risk is predicted by low rather than high homoarginine levels), which makes it plausible to normalize systemic homoarginine levels via oral supplementation. The emergence of homoarginine as a potentially treatable protective cardiovascular risk factor has generated a wave of hope in the field of cardiovascular prevention. Herein, we review the biochemistry, physiology, and metabolism of homoarginine, summarize the strengths and weaknesses of the epidemiological evidence linking homoarginine to cardiovascular disease and its potential protective cardiovascular effects, and identify priorities for future research needed to define the clinical utility of homoarginine as a prognostic factor and therapeutic target in cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.118.312218DOI Listing
May 2019

Beta-Aminoisobutyric Acid as a Novel Regulator of Carbohydrate and Lipid Metabolism.

Nutrients 2019 Feb 28;11(3). Epub 2019 Feb 28.

University Center for Vascular Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.

The prevalence and incidence of metabolic syndrome is reaching pandemic proportions worldwide, thus warranting an intensive search for novel preventive and treatment strategies. Recent studies have identified a number of soluble factors secreted by adipocytes and myocytes (adipo-/myokines), which link sedentary life style, abdominal obesity, and impairments in carbohydrate and lipid metabolism. In this review, we discuss the metabolic roles of the recently discovered myokine β-aminoisobutyric acid (BAIBA), which is produced by skeletal muscle during physical activity. In addition to physical activity, the circulating levels of BAIBA are controlled by the mitochondrial enzyme alanine: glyoxylate aminotransferase 2 (AGXT2), which is primarily expressed in the liver and kidneys. Recent studies have shown that BAIBA can protect from diet-induced obesity in animal models. It induces transition of white adipose tissue to a "beige" phenotype, which induces fatty acids oxidation and increases insulin sensitivity. While the exact mechanisms of BAIBA-induced metabolic effects are still not well understood, we discuss some of the proposed pathways. The reviewed data provide new insights into the connection between physical activity and energy metabolism and suggest that BAIBA might be a potential novel drug for treatment of the metabolic syndrome and its cardiovascular complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11030524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470580PMC
February 2019

ADMA reduction does not protect mice with streptozotocin-induced diabetes mellitus from development of diabetic nephropathy.

Atheroscler Suppl 2017 Nov 1;30:319-325. Epub 2017 Jun 1.

Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.

Background And Aims: Cardiovascular disease is the major cause of morbidity and mortality in the world. Diabetes and its complications, such as diabetic nephropathy, dramatically increase cardiovascular risk. Association studies suggest that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, plays a role in the pathogenesis of diabetic nephropathy. The major pathway of ADMA catabolism is hydrolysis by dimethylarginine dimethylaminohydrolase 1 (DDAH1). The goal of this study was to test the hypothesis that lowering ADMA by overexpression of DDAH1 protects from development of diabetic nephropathy.

Methods: Diabetes was induced with streptozotocin (STZ) in wild type and DDAH1 transgenic mice. Healthy mice served as controls. Mice were sacrificed after 20 weeks of diabetes. ADMA levels were assessed by isotope-dilution tandem mass spectrometry, creatinine by standard laboratory methods and albumin by ELISA. Kidney tissues were stained for markers of glomerular cells, cell matrix, inflammation and cell proliferation.

Results: STZ led to development of diabetes in all injected mice. Transgenic overexpression of DDAH1 led to a decrease in plasma ADMA levels in healthy animals. Diabetic state itself did not lead to elevation of plasma ADMA levels. Diabetic mice of both genotypes developed albuminuria (27 and 25 vs. 9 and 6 μg albumin/mg creatinine) (p < 0.01). There were no changes in glomerular matrix expansion, podocyte injury, inflammatory or proliferative response.

Conclusions: STZ-induced diabetes led to the development of early features of diabetic nephropathy. Overexpression of DDAH1 and lowering of systemic ADMA levels did not prevent these changes, indicating that ADMA is not the major mediator of the early diabetic changes reflected by this experimental model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosissup.2017.05.031DOI Listing
November 2017

Diabetes-linked transcription factor HNF4α regulates metabolism of endogenous methylarginines and β-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2.

Sci Rep 2016 10 18;6:35503. Epub 2016 Oct 18.

University Center for Vascular Medicine, Technische Universität Dresden, 01307 Dresden, Germany.

Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 α (HNF4α) in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4α binding site. Direct binding of HNF4α to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1-6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4α as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4α deficiency might contribute to development of cardiovascular complications in diabetic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep35503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067591PMC
October 2016

A Novel Pathway for Metabolism of the Cardiovascular Risk Factor Homoarginine by alanine:glyoxylate aminotransferase 2.

Sci Rep 2016 10 18;6:35277. Epub 2016 Oct 18.

Institute of Clinical Pharmacology, Otto-von-Guericke University, Leipziger Str.44, 39120 Magdeburg, Germany.

Low plasma concentrations of L-homoarginine are associated with an increased risk of cardiovascular events, while homoarginine supplementation is protective in animal models of metabolic syndrome and stroke. Catabolism of homoarginine is still poorly understood. Based on the recent findings from a Genome Wide Association Study we hypothesized that homoarginine can be metabolized by alanine:glyoxylate aminotransferase 2 (AGXT2). We purified human AGXT2 from tissues of AGXT2 transgenic mice and demonstrated its ability to metabolize homoarginine to 6-guanidino-2-oxocaproic acid (GOCA). After incubation of HepG2 cells overexpressing AGXT2 with isotope-labeled homoarginine-d4 we were able to detect labeled GOCA in the medium. We injected wild type mice with labeled homoarginine and detected labeled GOCA in the plasma. We found that AGXT2 knockout (KO) mice have higher homoarginine and lower GOCA plasma levels as compared to wild type mice, while the reverse was true for AGXT2 transgenic (Tg) mice. In summary, we experimentally proved the presence of a new pathway of homoarginine catabolism - its transamination by AGXT2 with formation of GOCA and demonstrated that endogenous AGXT2 is required for maintenance of homoarginine levels in mice. Our findings may lead to development of novel therapeutic approaches for cardiovascular pathologies associated with homoarginine deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep35277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082758PMC
October 2016

Acetylation of asymmetric and symmetric dimethylarginine: an undercharacterized pathway of metabolism of endogenous methylarginines.

Nephrol Dial Transplant 2016 Jan 25;31(1):57-63. Epub 2015 Nov 25.

Institute of Clinical Pharmacology, Otto-von-Guericke University, Magdeburg, Germany.

Background: Increased levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are associated with cardiovascular and renal diseases. We and others have shown that both ADMA and SDMA can be Nα-acetylated to form asymmetric and symmetric Nα-acetyldimethylarginine (Ac-ADMA and Ac-SDMA). The current study further investigated this undercharacterized metabolic pathway.

Methods: ADMA and SDMA were infused in C57/BL6 mice for 3 days using osmotic minipumps. Half of the mice underwent bilateral nephrectomy 24 h before completion of the infusion. Plasma and tissue levels of Ac-ADMA and Ac-SDMA were detected by liquid chromatography-tandem mass spectrometry.

Results: ADMA and SDMA infusion resulted in a 3.6-fold increase in plasma Ac-ADMA and a 21-fold increase in plasma Ac-SDMA levels, respectively. Plasma Ac-ADMA and Ac-SDMA levels were dramatically increased after bilateral nephrectomy. The highest baseline tissue concentrations of Ac-ADMA and Ac-SDMA in wild-type mice were detected in the liver, kidney, small intestine, pancreas and spleen. Incubation of the tissue lysates with ADMA and SDMA resulted in increased levels of the corresponding Nα-acetylated products only in the liver, kidney and small intestine.

Conclusions: Our results show that overload of ADMA or SDMA leads to an increase in plasma Ac-ADMA and Ac-SDMA levels. This observation is consistent with the hypothesis that Ac-ADMA and Ac-SDMA are formed directly from ADMA and SDMA in vivo. The increase in plasma Ac-ADMA and Ac-SDMA concentrations after bilateral nephrectomy suggests that both compounds are predominantly eliminated via the kidneys. We demonstrated that acetylation of ADMA and SDMA occurs primarily in the liver, kidney and small intestine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfv390DOI Listing
January 2016