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Ramos-Rodríguez C, Rojas-Gomez A, Santos-Calderón LA, Ceruelo S, Ríos L, Ueland PM, Fernandez-Ballart JD, Salas-Huetos A, Murphy MM. The l-Arginine pathway may act as a mediator in the association between impaired one-carbon metabolism and hypertension. Biochimie 2025; 230:86-94. [PMID: 39549999 DOI: 10.1016/j.biochi.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 11/13/2024] [Accepted: 11/13/2024] [Indexed: 11/18/2024]
Abstract
Elevated fasting plasma total homocysteine (tHcy) and the methylenetetrahydrofolate reductase C677T polymorphism (rs1801133) have been associated with hypertension. Whether the l-Arginine pathway is involved, is unclear. We aimed to investigate whether the association between tHcy, the rs1801133 polymorphism and hypertension involves the l-Arginine pathway. THcy, plasma folate and cobalamin, erythrocyte glutathionine reductase activation coefficient, rs1801133 genotype, plasma l-Arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were determined in a cross-sectional study of 788 adults (aged 18 to 75), randomly selected from 2 town population registers. Participants participated in a medical checkup and provided a fasting blood sample. Associations between tHcy, rs1801133 genotype and l-Arginine pathway metabolites were assessed by multiple linear regression analysis and whether the tHcy and rs1801133 genotype are associated with hypertension via the l-Arginine pathway was investigated using mediation analysis. tHcy was positively associated with ADMA (B = 0.003; SE = 0.001; P < 0.001) and SDMA (B = 0.007; SE = 0.002; P < 0.001) and negatively associated with the l-Arginine/ADMA (B = -1.140; SE = 0.451; P < 0.05) and ADMA/SDMA (B = -0.006; SE = 0.003; P < 0.05) ratios. The MTHFR 677 CT vs CC genotype was negatively associated with ADMA (B = -0.013; SE = 0.007; P < 0.05) and with SDMA (B = -0.029; SE = 0.013; P < 0.05) in participants under 50 years. Each standard deviation increase (37.6) in the l-Arginine/ADMA ratio was associated with reduced hypertension risk (OR [95%CI], 0.6 [0.5, 0.8]). Mediation analysis showed that tHcy and ADMA were mediators in the association between the rs1801133 TT vs CC genotypes and hypertension. Our results support the l-Arginine pathway as a mediator in the association of impaired One-Carbon metabolism and hypertension.
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Affiliation(s)
- Carla Ramos-Rodríguez
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain.
| | - Alejandra Rojas-Gomez
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain.
| | - Luis A Santos-Calderón
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain.
| | | | - Lídia Ríos
- Hospital Lleuger Antoni de Gimbernat de Cambrils, Spain.
| | | | - Joan D Fernandez-Ballart
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain; CIBERobn ISCIII, Spain.
| | - Albert Salas-Huetos
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain; CIBERobn ISCIII, Spain.
| | - Michelle M Murphy
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain; CIBERobn ISCIII, Spain.
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Bekyarova GY, Vankova DG, Madjova VH, Bekyarov NA, Salim AS, Ivanova DG, Stoeva SM, Gerova DI, Kiselova-Kaneva YD. Association between Nfr2, HO-1, NF-kB Expression, Plasma ADMA, and Oxidative Stress in Metabolic Syndrome. Int J Mol Sci 2023; 24:17067. [PMID: 38069389 PMCID: PMC10707226 DOI: 10.3390/ijms242317067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Endothelial dysfunction is one of the major factors in the pathogenesis of metabolic syndrome (MetS), and its molecular mechanisms are not completely understood. The present study aimed to examine the connection between nuclear factor2-related factor2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), heme oxygenase 1 (HO-1), and plasma asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) in people with MetS. Participants in the study were as follows: with MetS (n = 30) and without MetS (Control) (n = 14). Expression of Nrf2, NF-kB, and HO-1 was measured in peripheral blood mononuclear cells (PBMCs). Plasma ADMA was determined using the ELISA technique and MDA via the thiobarbituric acid method. Our study showed that mRNA of NF-kB, Nrf2, and HO-1 levels in PBMCs in the MetS group were significantly higher than in the controls by 53%, 130%, and 185% (p < 0.05), respectively. Similarly, elevated levels of MDA (by 78%, p < 0.001) and ADMA (by 18.7%, p < 0.001) were established in the MetS group. Our findings show the importance of transcription factor Nrf2, playing an integral role in the protection of the endothelium, and of NF-κB, a transcription factor mediating the inflammatory response in MetS. Knowledge of complex cellular-molecular mechanisms would allow the use of biomarkers such as Nrf2, NF-kB, HO-1, and ADMA for the assessment of endothelial dysfunction in clinical practice.
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Affiliation(s)
- Ganka Y. Bekyarova
- Department of Physiology and Pathophysiology, Medical University of Varna, 9002 Varna, Bulgaria
| | - Deyana G. Vankova
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9002 Varna, Bulgaria (A.S.S.); (D.G.I.); (S.M.S.)
| | - Valentina H. Madjova
- Department of General Medicine, Medical University of Varna, 9002 Varna, Bulgaria; (V.H.M.)
| | - Nicolai A. Bekyarov
- Department of General Medicine, Medical University of Varna, 9002 Varna, Bulgaria; (V.H.M.)
| | - Ayshe S. Salim
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9002 Varna, Bulgaria (A.S.S.); (D.G.I.); (S.M.S.)
| | - Diana G. Ivanova
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9002 Varna, Bulgaria (A.S.S.); (D.G.I.); (S.M.S.)
| | - Stefka M. Stoeva
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9002 Varna, Bulgaria (A.S.S.); (D.G.I.); (S.M.S.)
| | - Daniela I. Gerova
- Department of Clinical Laboratory, Medical University Varna, 9002 Varna, Bulgaria
| | - Yoana D. Kiselova-Kaneva
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9002 Varna, Bulgaria (A.S.S.); (D.G.I.); (S.M.S.)
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Shestakova KM, Moskaleva NE, Boldin AA, Rezvanov PM, Shestopalov AV, Rumyantsev SA, Zlatnik EY, Novikova IA, Sagakyants AB, Timofeeva SV, Simonov Y, Baskhanova SN, Tobolkina E, Rudaz S, Appolonova SA. Targeted metabolomic profiling as a tool for diagnostics of patients with non-small-cell lung cancer. Sci Rep 2023; 13:11072. [PMID: 37422585 PMCID: PMC10329697 DOI: 10.1038/s41598-023-38140-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/04/2023] [Indexed: 07/10/2023] Open
Abstract
Lung cancer is referred to as the second most common cancer worldwide and is mainly associated with complex diagnostics and the absence of personalized therapy. Metabolomics may provide significant insights into the improvement of lung cancer diagnostics through identification of the specific biomarkers or biomarker panels that characterize the pathological state of the patient. We performed targeted metabolomic profiling of plasma samples from individuals with non-small cell lung cancer (NSLC, n = 100) and individuals without any cancer or chronic pathologies (n = 100) to identify the relationship between plasma endogenous metabolites and NSLC by means of modern comprehensive bioinformatics tools, including univariate analysis, multivariate analysis, partial correlation network analysis and machine learning. Through the comparison of metabolomic profiles of patients with NSCLC and noncancer individuals, we identified significant alterations in the concentration levels of metabolites mainly related to tryptophan metabolism, the TCA cycle, the urea cycle and lipid metabolism. Additionally, partial correlation network analysis revealed new ratios of the metabolites that significantly distinguished the considered groups of participants. Using the identified significantly altered metabolites and their ratios, we developed a machine learning classification model with an ROC AUC value equal to 0.96. The developed machine learning lung cancer model may serve as a prototype of the approach for the in-time diagnostics of lung cancer that in the future may be introduced in routine clinical use. Overall, we have demonstrated that the combination of metabolomics and up-to-date bioinformatics can be used as a potential tool for proper diagnostics of patients with NSCLC.
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Affiliation(s)
- Ksenia M Shestakova
- World-Class Research Center Digital Biodesign and Personalized Healthcare, I.M. Sechenov First Moscow State Medical University, Moscow, Russia, 119435
| | - Natalia E Moskaleva
- World-Class Research Center Digital Biodesign and Personalized Healthcare, I.M. Sechenov First Moscow State Medical University, Moscow, Russia, 119435
| | - Andrey A Boldin
- Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow Medical University, Moscow, Russia, 119435
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia, 119435
| | - Pavel M Rezvanov
- Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow Medical University, Moscow, Russia, 119435
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia, 119435
| | | | - Sergey A Rumyantsev
- Pirogov Russian National Research Medical University, Moscow, Russia, 117997
| | - Elena Yu Zlatnik
- National Medical Research Centre for Oncology (Rostov-On-Don, Russia), 14 Liniya, 63, Rostov-on-Don, Russia, 344019
| | - Inna A Novikova
- National Medical Research Centre for Oncology (Rostov-On-Don, Russia), 14 Liniya, 63, Rostov-on-Don, Russia, 344019
| | - Alexander B Sagakyants
- National Medical Research Centre for Oncology (Rostov-On-Don, Russia), 14 Liniya, 63, Rostov-on-Don, Russia, 344019
| | - Sofya V Timofeeva
- National Medical Research Centre for Oncology (Rostov-On-Don, Russia), 14 Liniya, 63, Rostov-on-Don, Russia, 344019
| | - Yuriy Simonov
- Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow Medical University, Moscow, Russia, 119435
| | - Sabina N Baskhanova
- World-Class Research Center Digital Biodesign and Personalized Healthcare, I.M. Sechenov First Moscow State Medical University, Moscow, Russia, 119435
| | - Elena Tobolkina
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1206, Geneva 4, Switzerland.
| | - Serge Rudaz
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1206, Geneva 4, Switzerland
| | - Svetlana A Appolonova
- Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow Medical University, Moscow, Russia, 119435
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia, 119435
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Münzel T, Daiber A. Vascular redox signaling, eNOS uncoupling and endothelial dysfunction in the setting of transportation noise exposure or chronic treatment with organic nitrates. Antioxid Redox Signal 2023; 38:1001-1021. [PMID: 36719770 PMCID: PMC10171967 DOI: 10.1089/ars.2023.0006] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
SIGNIFICANCE Cardiovascular disease and drug-induced health side effects are frequently associated with - or even caused by - an imbalance between the concentrations of reactive oxygen and nitrogen species (RONS) and antioxidants respectively determining the metabolism of these harmful oxidants. RECENT ADVANCES According to the "kindling radical" hypothesis, initial formation of RONS may further trigger the additional activation of RONS formation under certain pathological conditions. The present review will specifically focus on a dysfunctional, uncoupled endothelial nitric oxide synthase (eNOS) caused by RONS in the setting of transportation noise exposure or chronic treatment with organic nitrates, especially nitroglycerin. We will further describe the various "redox switches" that are proposed to be involved in the uncoupling process of eNOS. CRITICAL ISSUES In particular, the oxidative depletion of tetrahydrobiopterin (BH4), and S-glutathionylation of the eNOS reductase domain will be highlighted as major pathways for eNOS uncoupling upon noise exposure or nitroglycerin treatment. In addition, oxidative disruption of the eNOS dimer, inhibitory phosphorylation of eNOS at threonine or tyrosine residues, redox-triggered accumulation of asymmetric dimethylarginine (ADMA) and L-arginine deficiency will be discussed as alternative mechanisms of eNOS uncoupling. FUTURE DIRECTIONS The clinical consequences of eNOS dysfunction due to uncoupling on cardiovascular disease will be summarized also providing a template for future clinical studies on endothelial dysfunction caused by pharmacological or environmental risk factors.
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Affiliation(s)
- Thomas Münzel
- University Medical Center of the Johannes Gutenberg University Mainz, 39068, Cardiology I, Mainz, Rheinland-Pfalz, Germany;
| | - Andreas Daiber
- University Medical Center of the Johannes Gutenberg University Mainz, 39068, Cardiology I, Mainz, Rheinland-Pfalz, Germany;
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Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma Milla S, Zangara A, Candela CG. Oral Supplement Containing Hydroxytyrosol and Punicalagin Improves Dyslipidemia in an Adult Population without Co-Adjuvant Treatment: A Randomized, Double-Blind, Controlled and Crossover Trial. Nutrients 2022; 14:nu14091879. [PMID: 35565844 PMCID: PMC9103949 DOI: 10.3390/nu14091879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/22/2022] [Accepted: 04/26/2022] [Indexed: 12/04/2022] Open
Abstract
Hydroxytyrosol (HT) and punicalagin (PC) exert cardioprotective and antiatherosclerotic effects. This study evaluated the effect of an oral supplement containing HT and PC (SAx) on dyslipidemia in an adult population. A randomized, double-blind, controlled, crossover trial was conducted over a 20-week period. SAx significantly reduced the plasma levels of triglycerides (TG) in subjects with hypertriglyceridemia (≥150 mg/dL) (from 200.67 ± 51.38 to 155.33 ± 42.44 mg/dL; p < 0.05), while no such effects were observed in these subjects after the placebo. SAx also significantly decreased the plasma levels of low-density lipoprotein cholesterol (LDL-C) in subjects with high plasma levels of LDL-C (≥160 mg/dL) (from 179.13 ± 16.18 to 162.93 ± 27.05 mg/dL; p < 0.01), while no such positive effect was observed with the placebo. In addition, the placebo significantly reduced the plasma levels of high-density lipoprotein cholesterol (HDL-C) in the total population (from 64.49 ± 12.65 to 62.55 ± 11.57 mg/dL; p < 0.05), while SAx significantly increased the plasma levels of HDL-C in subjects with low plasma levels of HDL-C (<50 mg/dL) (from 44.25 ± 3.99 to 48.00 ± 7.27 mg/dL; p < 0.05). In conclusion, the supplement containing HT and PC exerted antiatherosclerotic and cardio-protective effects by considerably improving dyslipidemia in an adult population, without co-adjuvant treatment or adverse effects.
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Affiliation(s)
- Rebeca Quirós-Fernández
- Nutrition Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain;
- Correspondence: (R.Q.-F.); (B.P.-L.)
| | - Bricia López-Plaza
- Nutrition Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain;
- Correspondence: (R.Q.-F.); (B.P.-L.)
| | - Laura M. Bermejo
- Nutrition Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain;
| | - Samara Palma Milla
- Nutrition Department, Hospital University La Paz, 28046 Madrid, Spain; (S.P.M.); (C.G.C.)
| | - Andrea Zangara
- Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC 3122, Australia;
- Euromed S.A., C/Rec de Dalt, 21-23, Pol. Ind. Can Magarola, 08100 Mollet del Valles, Spain
| | - Carmen Gómez Candela
- Nutrition Department, Hospital University La Paz, 28046 Madrid, Spain; (S.P.M.); (C.G.C.)
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Zhong Y, Zhang Z, Chen X. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway. Open Med (Wars) 2022; 17:1949-1964. [PMID: 36561848 PMCID: PMC9743197 DOI: 10.1515/med-2022-0584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 09/07/2022] [Accepted: 10/02/2022] [Indexed: 12/14/2022] Open
Abstract
miR-21 has been confirmed to be overexpressed in neonatal rat lungs with hyperoxia-mediated bronchopulmonary dysplasia (BPD). The specific function of miR-21 in BPD is still unclear. We established the hyperoxia-induced BPD rat model in vivo and the hyperoxia-induced pulmonary microvascular endothelial cells (PMVECs) model in vitro. Transwell assay was utilized to detect the migratory capability of PMVECs. Tube formation assay was utilized to measure angiogenesis ability. ELISA was utilized to test nitric oxide (NO) production and the intracellular and extracellular Asymmetric Dimethylarginine (ADMA) concentration. Furthermore, the interaction between miR-21 and dimethylarginine dimethylaminohydrolase 1 (DDAH1) was evaluated using luciferase reporter assay. We found that miR-21 expression in PMVECs was increased by hyperoxia stimulation. Inhibition of miR-21 improved the migratory and angiogenic activities of PMVECs and overexpression of miR-21 exerted the opposite effects. Furthermore, knockdown of miR-21 increased NO production and decreased intracellular and extracellular ADMA concentration in hyperoxia-treated PMVECs. Next we proved that miR-21 could bind to DDAH1 and negatively regulate its expression. Rescues assays showed that DDAH1 knockdown reversed the effects of miR-21 depletion on hyperoxia-mediated PMVEC functions, NO production, and ADMA concentration. Importantly, miR-21 downregulation restored alveolarization and vascular density in BPD rats. This study demonstrates that inhibition of miR-21 improves pulmonary vascular responses in BPD by targeting the DDAH1/ADMA/NO pathway.
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Affiliation(s)
- Ying Zhong
- Department of Child Health Care, The First Affiliated Hospital of Nanjing Medical University, 368 Jiangdong North Road, Nanjing 210036, Jiangsu, China
| | - Zhiqun Zhang
- Department of Neonatology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, China
| | - Xiaoqing Chen
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210036, Jiangsu, China
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Groves HK, Lee H. Perioperative Management of Renal Failure and Renal Transplant. Perioper Med (Lond) 2022. [DOI: 10.1016/b978-0-323-56724-4.00019-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Ertelt A, Merle R, Stumpff F, Bollinger L, Liertz S, Weber C, Gehlen H. Evaluation of Different Blood Parameters From Endurance Horses Competing at 160 km. J Equine Vet Sci 2021; 104:103687. [PMID: 34416987 DOI: 10.1016/j.jevs.2021.103687] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 06/06/2021] [Accepted: 06/07/2021] [Indexed: 01/02/2023]
Abstract
The purpose of this study was to assess a change in different blood parameters before and after a 160 km endurance race and to evaluate differences in cardiac biomarkers between horses that completed the race and horses that did not. The study population consisted of 52 healthy endurance horses. Horses participating in the study were assigned to three groups: horses that successfully completed the race ("finishers"), horses that failed to qualify at the veterinary check for primarily metabolic reasons ("metabolic") and horses that failed to qualify at the veterinary check for primarily gait related reasons ("gait related"). The latter two groups were combined to form a final group of "non-finishers" that were excluded for either "gait related" or "metabolic" disorders. Venous blood samples were taken before and after the endurance race. Serum and EDTA-plasma were analyzed for cardiac troponin I (cTNI), heart fatty acid binding protein (HFABP), alpha-hydroxybutyrate dehydrogenase (α-HBDH), atrial natriuretic peptide (ANP), lactate dehydrogenase (LDH), symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). Lactate dehydrogenase (P = .001), SDMA (P= .001) and ADMA (P= .002) increased significantly after the endurance race in the finisher group. A significant increase in cTNI and α-HBDH concentration after the endurance race compared to the values before the endurance race was detected in the finisher (P= .001, P= .001) and gait related group (P= .002, P= .007). The longer the distance completed, the more these five blood parameters increased. No differences between the groups could be found and none of the measured blood parameters showed significant differences among groups before or after racing.
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Affiliation(s)
- Antonia Ertelt
- Equine Clinic, Internal Medicine, Freie Universitaet Berlin, Berlin, Germany.
| | - Roswitha Merle
- Institute for Veterinary Epidemiology and Biostatistics, Freie Universitaet Berlin, Berlin, Germany
| | - Friederike Stumpff
- Institute of Veterinary Physiology, Freie Universitaet Berlin, Berlin, Germany
| | - Lena Bollinger
- Equine Clinic, Internal Medicine, Freie Universitaet Berlin, Berlin, Germany
| | - Sarah Liertz
- Equine Clinic, Internal Medicine, Freie Universitaet Berlin, Berlin, Germany
| | - Corinna Weber
- Laboklin Veterinary Diagnostic Laboratory, Bad Kissingen, Germany
| | - Heidrun Gehlen
- Equine Clinic, Internal Medicine, Freie Universitaet Berlin, Berlin, Germany
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Hou M, Cao L, Ding Y, Chen Y, Wang B, Shen J, Zhou W, Huang J, Xu Q, Lv H, Sun L. Neutrophil to Lymphocyte Ratio Is Increased and Associated With Left Ventricular Diastolic Function in Newly Diagnosed Essential Hypertension Children. Front Pediatr 2021; 9:576005. [PMID: 34095018 PMCID: PMC8169980 DOI: 10.3389/fped.2021.576005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 04/06/2021] [Indexed: 01/07/2023] Open
Abstract
Aim: Hypertension is associated with cardiac structural and functional changes, including left ventricular hypertrophy (LVH) and LV systolic dysfunction diastolic dysfunction. Neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker associated with cardiovascular diseases. The current study aimed to evaluate NLR in children with newly diagnosed essential hypertension and its relationship between blood pressure and cardiac changes. Methods and Subjects: Sixty-five children with newly diagnosed essential hypertension and 54 healthy children were included. Clinical characteristics, blood cell counts, and biochemical parameters were collected. LVH was assessed by calculation of LV mass index (LVMI), and LV systolic function was evaluated by measuring LV ejection fraction and fractional shortening. LV diastolic function was primarily assessed with E/E' ratio by Doppler and echocardiography. Results: The hypertension children had significantly higher LVMI and E/E' ratio than the controls, whereas there was no difference in LV systolic function between the two groups. The NLR was significantly higher in the hypertension group than the control group. Moreover, NLR was positively correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels in the hypertension group. Additionally, a significantly positive correlation between NLR and E/E' ratio was found in the hypertension group. However, NLR was not related to LVH and LV systolic function indicators in hypertension children. Conclusion: NLR is elevated in hypertension children, and it is associated positively with office blood pressure levels. Moreover, NLR may help assess LV diastolic function in hypertension children.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Ling Sun
- Department of Cardiology, Children’s Hospital of Soochow University, Suzhou, China
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Stamerra CA, Del Pinto R, di Giosia P, Ferri C, Sahebkar A. Anderson-Fabry Disease: From Endothelial Dysfunction to Emerging Therapies. Adv Pharmacol Pharm Sci 2021; 2021:5548445. [PMID: 34095851 PMCID: PMC8137293 DOI: 10.1155/2021/5548445] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/07/2021] [Indexed: 12/30/2022] Open
Abstract
The Anderson-Fabry disease is a rare, X-linked, multisystemic, progressive lysosomal storage disease caused by α-galactosidase A total or partial deficiency. The resulting syndrome is mainly characterized by early-onset autonomic neuropathy and life-threatening multiorgan involvement, including renal insufficiency, heart disease, and early stroke. The enzyme deficiency leads to tissue accumulation of the glycosphingolipid globotriaosylceramide and its analogues, but the mechanisms linking such accumulation to organ damage are only partially understood. In contrast, enzyme replacement and chaperone therapies are already fully available to patients and allow substantial amelioration of quality and quantity of life. Substrate reduction, messenger ribonucleic acid (mRNA)-based, and gene therapies are also on the horizon. In this review, the clinical scenario and molecular aspects of Anderson-Fabry disease are described, along with updates on disease mechanisms and emerging therapies.
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Affiliation(s)
- Cosimo A. Stamerra
- University of L'Aquila, Department of Life, Health and Environmental Sciences, Building Delta 6-San Salvatore Hospital, Via Vetoio, Coppito, L'Aquila 67100, Italy
| | - Rita Del Pinto
- University of L'Aquila, Department of Life, Health and Environmental Sciences, Building Delta 6-San Salvatore Hospital, Via Vetoio, Coppito, L'Aquila 67100, Italy
| | - Paolo di Giosia
- University of L'Aquila, Department of Life, Health and Environmental Sciences, Building Delta 6-San Salvatore Hospital, Via Vetoio, Coppito, L'Aquila 67100, Italy
| | - Claudio Ferri
- University of L'Aquila, Department of Life, Health and Environmental Sciences, Building Delta 6-San Salvatore Hospital, Via Vetoio, Coppito, L'Aquila 67100, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Ye J, Dai Y, Mao H, Zheng W, Zhang J. Prognostic value of asymmetric dimethylarginine in patients with coronary artery disease: A meta-analysis. Nitric Oxide 2021; 109-110:50-56. [PMID: 33684543 DOI: 10.1016/j.niox.2021.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 02/06/2021] [Accepted: 03/02/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Studies regarding the predictive utility of the blood level of asymmetric dimethylarginine (ADMA) in patients with coronary artery disease (CAD) have yielded the conflicting findings. This meta-analysis sought to evaluate the prognostic value of blood ADMA level in CAD patients. METHODS Potentially relevant studies were identified by searching PubMed and Embase database until August 12, 2020. Cohort studies evaluating the association of blood ADMA level with all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACEs) were included. A random effect model was applied to pool the multivariable-adjusted risk ratio (RR) and 95% confidence intervals (CI) for the highest versus lowest ADMA level. RESULTS Data were retrieved from 11 studies enrolling a total of 9496 CAD patients. When compared the highest to the lowest ADMA level, the pooled RR was 2.10 (95% CI 1.46-3.02) for all-cause mortality, 2.49 (95% CI 1.34-4.65) for cardiovascular mortality, and 1.71 (95% CI 1.27-2.32) for MACEs, respectively. However, subgroup analysis showed that there were no significant association between elevated ADMA level and all-cause mortality in acute coronary syndrome (RR 2.11; 95% CI 0.93-4.78) and follow up ≤ 1 year (RR 2.15; 95% CI 0.56-8.25) subgroup. CONCLUSIONS Elevated blood ADMA level is possibly an independent predictor of all-cause mortality, cardiovascular mortality, and MACEs in CAD patients. Measurement of blood level of ADMA may improve risk classification of CAD. However, these findings should be interpreted with caution because of the limited number of studies included.
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Affiliation(s)
- Jianfei Ye
- Department of Cardiology, Ningbo Fourth Hospital, Ningbo, 315700, Zhejiang, China.
| | - Yuxiang Dai
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease, ZhongShan Hospital, Fudan University, 200032, Shanghai, China.
| | - Huanhao Mao
- Department of Cardiology, Ningbo Fourth Hospital, Ningbo, 315700, Zhejiang, China
| | - Weifeng Zheng
- Department of Cardiology, Ningbo Fourth Hospital, Ningbo, 315700, Zhejiang, China
| | - Jing Zhang
- Department of Cardiology, Ningbo Fourth Hospital, Ningbo, 315700, Zhejiang, China
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12
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Craig A, Mels CMC, Schutte AE, Bollenbach A, Tsikas D, Schwedhelm E, Kruger R. Urinary albumin-to-creatinine ratio is inversely related to nitric oxide synthesis in young black adults: the African-PREDICT study. Hypertens Res 2020; 44:71-79. [PMID: 32681162 DOI: 10.1038/s41440-020-0514-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 06/21/2020] [Indexed: 01/30/2023]
Abstract
Hypertension is common in black populations and is known to be associated with low nitric oxide (NO) bioavailability. We compared plasma and urinary NO-related markers and plasma creatine kinase (CK) levels between young healthy black and white adults along with the associations of these markers with the urinary albumin-to-creatinine ratio (uACR), which is a surrogate marker of endothelial and kidney function. We included 1105 participants (20-30 years). We measured the uACR, plasma CK, plasma and urinary arginine, homoarginine, asymmetric (ADMA) and symmetric dimethylarginine (SDMA), urinary ornithine/citrulline, nitrate and nitrite, and malondialdehyde (MDA). In addition, the urinary nitrate-to-nitrite ratio (UNOxR) was calculated and used as a measure of circulating NO bioavailability. The uACR was comparable between the groups, yet the black group had lower urinary nitrate (by -15%) and UNOxR values (by -18%) (both p ≤ 0.001), higher plasma (by +9.6%) and urinary (by +5.9%) arginine (both p ≤ 0.004), higher plasma (by +13%) and urinary (by +3.7%) ADMA (both p ≤ 0.033), and higher CK (by +9.5%) and MDA (by +19%) (both p < 0.001) compared with white adults. Plasma and urinary homoarginine were similar between the groups. In the multiple regression analysis, we confirmed the inverse associations of the uACR with both plasma (adj. R2 = 0.066; β = -0.209; p = 0.005) and urinary (adj. R2 = 0.066; β = -0.149; p = 0.010) homoarginine and with the UNOxR (adj. R2 = 0.060; β = -0.122; p = 0.031) in the black group only. The overall less favorable NO profile and higher CK and MDA levels in the black cohort along with the adverse associations with the uACR may reflect the vulnerability of this cohort to the early development of hypertension.
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Affiliation(s)
- Ashleigh Craig
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa
| | - Catharina M C Mels
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa.,MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
| | - Aletta E Schutte
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa.,MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa.,School of Public Health and Community Medicine, University of New South Wales and The George Institute for Global Health, Sydney, Australia
| | - Alexander Bollenbach
- Institute of Toxicology, Core Unit Proteomics, Hannover Medical School, Hannover, Germany
| | - Dimitrios Tsikas
- Institute of Toxicology, Core Unit Proteomics, Hannover Medical School, Hannover, Germany
| | - Edzard Schwedhelm
- Institute of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Deutsches Zentrum fuer Herz-Kreislauf-Forschung E.V. (DZHK), Partner Site Hamburg/Kiel/Lüebeck, Hamburg, Germany
| | - Ruan Kruger
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa. .,MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa.
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13
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Daiber A, Kröller-Schön S, Oelze M, Hahad O, Li H, Schulz R, Steven S, Münzel T. Oxidative stress and inflammation contribute to traffic noise-induced vascular and cerebral dysfunction via uncoupling of nitric oxide synthases. Redox Biol 2020; 34:101506. [PMID: 32371009 PMCID: PMC7327966 DOI: 10.1016/j.redox.2020.101506] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/02/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023] Open
Abstract
Environmental pollution and non-chemical stressors such as mental stress or traffic noise exposure are increasingly accepted as health risk factors with substantial contribution to chronic noncommunicable diseases (e.g. cardiovascular, metabolic and mental). Whereas the mechanisms of air pollution-mediated adverse health effects are well characterized, the mechanisms of traffic noise exposure are not completely understood, despite convincing clinical and epidemiological evidence for a significant contribution of environmental noise to overall mortality and disability. The initial mechanism of noise-induced cardiovascular, metabolic and mental disease is well defined by the „noise reaction model“ and consists of neuronal activation involving the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathetic nervous system, followed by a classical stress response via cortisol and catecholamines. Stress pathways are initiated by noise-induced annoyance and sleep deprivation/fragmentation. This review highlights the down-stream pathophysiology of noise-induced mental stress, which is based on an induction of inflammation and oxidative stress. We highlight the sources of reactive oxygen species (ROS) involved and the known targets for noise-induced oxidative damage. Part of the review emphasizes noise-triggered uncoupling/dysregulation of endothelial and neuronal nitric oxide synthase (eNOS and nNOS) and its central role for vascular dysfunction.
Exposure to (traffic) noise causes non-auditory (indirect) cardiovascular and cerebral health harms via neuronal activation. Noise activates the HPA axis and sympathetic nervous system increasing levels of stress hormones, vasoconstrictors and ROS. Noise induces inflammation and stimulates several ROS sources leading to cerebral and cardiovascular oxidative damage. Noise leads to eNOS and nNOS uncoupling contributing to cardiometabolic disease and cognitive impairment.
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Affiliation(s)
- Andreas Daiber
- Center for Cardiology, Molecular Cardiology, University Medical Center, Mainz, Germany; Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr. 1, 55131, Mainz, Germany.
| | - Swenja Kröller-Schön
- Center for Cardiology, Molecular Cardiology, University Medical Center, Mainz, Germany
| | - Matthias Oelze
- Center for Cardiology, Molecular Cardiology, University Medical Center, Mainz, Germany
| | - Omar Hahad
- Center for Cardiology, Molecular Cardiology, University Medical Center, Mainz, Germany; Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr. 1, 55131, Mainz, Germany
| | - Huige Li
- Department of Pharmacology, University Medical Center, Mainz, Germany
| | - Rainer Schulz
- Institute of Physiology, Justus-Liebig University, Giessen, Germany
| | - Sebastian Steven
- Center for Cardiology, Molecular Cardiology, University Medical Center, Mainz, Germany
| | - Thomas Münzel
- Center for Cardiology, Molecular Cardiology, University Medical Center, Mainz, Germany; Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr. 1, 55131, Mainz, Germany.
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14
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Sutton EF, Gemmel M, Powers RW. Nitric oxide signaling in pregnancy and preeclampsia. Nitric Oxide 2020; 95:55-62. [DOI: 10.1016/j.niox.2019.11.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/10/2019] [Accepted: 11/22/2019] [Indexed: 01/08/2023]
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15
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Daiber A, Xia N, Steven S, Oelze M, Hanf A, Kröller-Schön S, Münzel T, Li H. New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease. Int J Mol Sci 2019; 20:ijms20010187. [PMID: 30621010 PMCID: PMC6337296 DOI: 10.3390/ijms20010187] [Citation(s) in RCA: 187] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 12/27/2018] [Accepted: 12/28/2018] [Indexed: 02/07/2023] Open
Abstract
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.
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Affiliation(s)
- Andreas Daiber
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany.
| | - Ning Xia
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Sebastian Steven
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Matthias Oelze
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Alina Hanf
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Swenja Kröller-Schön
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Thomas Münzel
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany.
| | - Huige Li
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
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16
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Loso J, Lund N, Avanesov M, Muschol N, Lezius S, Cordts K, Schwedhelm E, Patten M. Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy. Front Cardiovasc Med 2018; 5:108. [PMID: 30159316 PMCID: PMC6104487 DOI: 10.3389/fcvm.2018.00108] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 07/17/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Fabry disease (FD) is characterized by early development of vasculopathy and endothelial dysfunction. However, it is unclear whether these findings also play a pivotal role in cardiac manifestation. As Fabry cardiomyopathy (FC) is the leading cause of death in FD, we aimed to gather a better insight in pathological mechanisms of the disease. Methods: Serum samples were obtained from 17 healthy controls, 15 FD patients with and 7 without FC. FC was defined by LV wall thickening of >12 mm in cardiac magnetic resonance imaging and serum level of proBNP, high sensitive Troponin T (hsT), and globotriaosylsphingosine (lyso-GB3) were obtained. A multiplex ELISA-Assay for 23 different angiogenesis markers was performed in pooled samples. Markers showing significant differences among groups were further analyzed in single samples using specific Elisa antibody assays. L-homoarginine (hArg), L-arginine, asymmetric (ADMA), and symmetric Dimethylarginine (SDMA) were quantified by liquid chromatography—mass spectrometry. Results: Angiostatin and matrix metalloproteinase 9 (MMP-9) were elevated in FD patients compared to controls independently of the presence of FC (angiostatin: 98 ± 25 vs. 75 ± 15 ng/mL; p = 0.001; MMP-9: 8.0 ± 3.4 vs. 5.0 ± 2.4 μg/mL; p = 0.002). SDMA concentrations were highest in patients with FC (0.90 ± 0.64 μmol/l) compared to patients without (0.57 ± 0.10 μmol/l; p = 0.027) and vs. controls (0.58 ± 0.12 μmol/l; p = 0.006) and was positively correlated with indexed LV-mass (r = 0.61; p = 0.003), hsT (r = 0.56, p = 0.008), and lyso-Gb3 (r = 0.53, p = 0.013). Accordingly, the ratio of L-homoarginine to SDMA (hArg/SDMA) was lowest in patients with FC (2.63 ± 1.78) compared to controls (4.16 ± 1.44; p = 0.005). For L-arginine, hArg and ADMA no significant differences among groups could be detected, although a trend toward higher ADMA and lower hArg levels could be observed in the FC group. Furthermore, a significant relationship between kidney and cardiac function could be revealed (p = 0.045). Conclusion: Elevated MMP-9 and angiostatin levels suggest an increased extracellular matrix turnover in FD patients. Furthermore, endothelial dysfunction may also be involved in FC, as SDMA and hArg/SDMA are altered in these patients.
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Affiliation(s)
- Jefferson Loso
- Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
| | - Natalie Lund
- Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
| | - Maxim Avanesov
- Department of Diagnostic and Interventional Radiology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany
| | - Nicole Muschol
- Department of Pediatrics, University Medical Center Hamburg- Eppendorf, Hamburg, Germany
| | - Susanne Lezius
- Department of Medical Biometry and Epidemiology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany
| | - Kathrin Cordts
- Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany.,DZHK (German Center for Cardiovascular Research e.V.), Hamburg, Germany
| | - Edzard Schwedhelm
- Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany.,DZHK (German Center for Cardiovascular Research e.V.), Hamburg, Germany
| | - Monica Patten
- Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.,DZHK (German Center for Cardiovascular Research e.V.), Hamburg, Germany
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Abstract
PURPOSE OF REVIEW Since identification of aspartate aminotransferase as the first cardiac biomarker in the 1950s, there have been a number of new markers used for myocardial damage detection over the decades. There have also been several generations of troponin assays, each with progressively increasing sensitivity for troponin detection. Accordingly, the "standard of care" for myocardial damage detection continues to change. The purpose of this paper is to review the clinical utility, biological mechanisms, and predictive value of these various biomarkers in contemporary clinical studies. RECENT FINDINGS As of this writing, a fifth "next" generation troponin assay has now been cleared by the US Food and Drug Administration for clinical use in the USA for subjects presenting with suspected acute coronary syndromes. Use of these high-sensitivity assays has allowed for earlier detection of myocardial damage as well as greater negative predictive value for infarction after only one or two serial measurements. Recent algorithms utilizing these assays have allowed for more rapid rule-out of myocardial infarction in emergency department settings. In this review, we discuss novel assays available for the risk assessment of subjects presenting with chest pain, including both the "next generation" cardiac troponin assays as well as other novel biomarkers. We review the biological mechanisms for these markers, and explore the positive and negative predictive value of the assays in clinical studies, where reported. We also discuss the potential use of these new markers within the context of future clinical care in the modern era of higher sensitivity troponin testing. Finally, we discuss advances in new platforms (e.g., mass spectrometry) that historically have not been considered for rapid in vitro diagnostic capabilities, but that are taking a larger role in clinical diagnostics, and whose prognostic value and power promise to usher in new markers with potential for future clinical utility in acute coronary syndrome.
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Affiliation(s)
- Haitham M Ahmed
- Preventive Cardiology and Rehabilitation, Cleveland Clinic, Heart and Vascular Institute, 9500 Euclid Ave, Desk JB1, Cleveland, OH, 44195, USA.
| | - Stanley L Hazen
- Preventive Cardiology and Rehabilitation, Cleveland Clinic, Heart and Vascular Institute, 9500 Euclid Ave, Desk JB1, Cleveland, OH, 44195, USA
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA
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18
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Kukla M, Waluga M, Żorniak M, Berdowska A, Wosiewicz P, Sawczyn T, Bułdak RJ, Ochman M, Ziora K, Krzemiński T, Hartleb M. Serum omentin and vaspin levels in cirrhotic patients with and without portal vein thrombosis. World J Gastroenterol 2017; 23:2613-2624. [PMID: 28465646 PMCID: PMC5394525 DOI: 10.3748/wjg.v23.i14.2613] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate serum omentin and vaspin levels in cirrhotic patients; and to assess the relationship of these levels with hemostatic parameters, metabolic abnormalities, cirrhosis severity and etiology.
METHODS Fifty-one cirrhotic patients (17 with portal vein thrombosis) were analyzed. Serum omentin and vaspin levels were measured with commercially available direct enzyme-linked immunosorbent assays (ELISAs). To assess platelet activity, the following tests were performed using a MULTIPLATE®PLATELET FUNCTION ANALYZER: (1) an ADP-induced platelet activation test; (2) a cyclooxygenase dependent aggregation test (ASPI test); (3) a von Willebrand factor and glycoprotein Ib-dependent aggregation (using ristocetin) test (RISTO test); and (4) a test for thrombin receptor-activating peptide-6 induced activation of the thrombin receptor, which is sensitive to IIb/IIIa receptor antagonists.
RESULTS Omentin, but not vaspin, serum concentrations were significantly decreased in patients with portal vein thrombosis (PVT) (P = 0.01). Prothrombin levels were significantly increased in patients with PVT (P = 0.01). The thrombin receptor activating peptide (TRAP) test results were significantly lower in the PVT group (P = 0.03). No significant differences in adipokines serum levels were found regarding the etiology or severity of liver cirrhosis assessed according to the Child-Pugh or Model of End-Stage Liver Disease (MELD) scores. There was a significant increase in the TRAP (P = 0.03), ASPI (P = 0.001) and RISTO high-test (P = 0.02) results in patients with lower MELD scores. Serum omentin and vaspin levels were significantly down-regulated in patients without insulin resistance (P = 0.03, P = 0.02, respectively). A positive relationship between omentin and vaspin levels were found both when all of the patients were analyzed (r = 0.41, P = 0.01) and among those with PVT (r = 0.94, P < 0.001).
CONCLUSION Serum omentin levels are increased in patients without PVT. Cirrhosis origin and grade do not affect omentin and vaspin levels. The analyzed adipokines do not influence platelet activity.
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19
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Cui K, Luan Y, Tang Z, Rao K, Wang T, Chen Z, Wang S, Liu J, Wang D. Involvement of DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP Pathways in Human Tissue Kallikrein 1 Protecting Erectile Function in Aged Rats. PLoS One 2017; 12:e0170427. [PMID: 28103290 PMCID: PMC5245815 DOI: 10.1371/journal.pone.0170427] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 01/04/2017] [Indexed: 02/07/2023] Open
Abstract
Our previous studies had reported that Human Tissue Kallikrein 1 (hKLK1) preserved erectile function in aged transgenic rats, while the detailed mechanism of hKLK1 protecting erectile function in aged rats through activation of cGMP and cAMP was not mentioned. To explore the latent mechanism, male wild-type Sprague-Dawley rats (WTR) and transgenic rats harboring the hKLK1 gene (TGR) were fed to 4 and 18 months old and divided into four groups: young WTR (yWTR) as the control, aged WTR (aWTR), aged TGR (aTGR) and aged TGRs with HOE140 (aTGRH). Erectile function of all rats was evaluated by cavernous nerve electrostimulation method and measured by the ratio of intracavernous pressure/ mean arterial pressure (ICP/MAP) in rats. Expression levels of cAMP and cGMP were assessed, and related signaling pathways were detected by western blot, immunohistochemistry and RT-PCR. Our experiment results showed erectile function of the aWTR group and aTGRH group was lower compared with those of other two groups. Also, expression levels of cAMP and cGMP were significantly lower than those of other two groups. Moreover, expressions of related signaling pathways including DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP were also downregulated in the corpus cavernosum of rats in aWTR group. Our finding revealed hKLK1 played a protective role in age-related ED. The DDAH/ADMA/NOS/cGMP and COX-2/PTGIS/cAMP pathways that were linked to the mechanism hKLK1 could increase the levels of cGMP and cAMP, which might provide novel therapy targets for age-related ED.
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Affiliation(s)
- Kai Cui
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yang Luan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhe Tang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ke Rao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhong Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- * E-mail: (JL); (DW)
| | - Daowen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- * E-mail: (JL); (DW)
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20
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Kumar S, Sun X, Noonepalle SK, Lu Q, Zemskov E, Wang T, Aggarwal S, Gross C, Sharma S, Desai AA, Hou Y, Dasarathy S, Qu N, Reddy V, Lee SG, Cherian-Shaw M, Yuan JXJ, Catravas JD, Rafikov R, Garcia JGN, Black SM. Hyper-activation of pp60 Src limits nitric oxide signaling by increasing asymmetric dimethylarginine levels during acute lung injury. Free Radic Biol Med 2017; 102:217-228. [PMID: 27838434 PMCID: PMC5449193 DOI: 10.1016/j.freeradbiomed.2016.11.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 10/17/2016] [Accepted: 11/04/2016] [Indexed: 12/22/2022]
Abstract
The molecular mechanisms by which the endothelial barrier becomes compromised during lipopolysaccharide (LPS) mediated acute lung injury (ALI) are still unresolved. We have previously reported that the disruption of the endothelial barrier is due, at least in part, to the uncoupling of endothelial nitric oxide synthase (eNOS) and increased peroxynitrite-mediated nitration of RhoA. The purpose of this study was to elucidate the molecular mechanisms by which LPS induces eNOS uncoupling during ALI. Exposure of pulmonary endothelial cells (PAEC) to LPS increased pp60Src activity and this correlated with an increase in nitric oxide (NO) production, but also an increase in NOS derived superoxide, peroxynitrite formation and 3-nitrotyrosine (3-NT) levels. These effects could be simulated by the over-expression of a constitutively active pp60Src (Y527FSrc) mutant and attenuated by over-expression of dominant negative pp60Src mutant or reducing pp60Src expression. LPS induces both RhoA nitration and endothelial barrier disruption and these events were attenuated when pp60Src expression was reduced. Endothelial NOS uncoupling correlated with an increase in the levels of asymmetric dimethylarginine (ADMA) in both LPS exposed and Y527FSrc over-expressing PAEC. The effects in PAEC were also recapitulated when we transiently over-expressed Y527FSrc in the mouse lung. Finally, we found that the pp60-Src-mediated decrease in DDAH activity was mediated by the phosphorylation of DDAH II at Y207 and that a Y207F mutant DDAH II was resistant to pp60Src-mediated inhibition. We conclude that pp60Src can directly inhibit DDAH II and this is involved in the increased ADMA levels that enhance eNOS uncoupling during the development of ALI.
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Affiliation(s)
- Sanjiv Kumar
- Vascular Biology Center and the Center for Biotechnology & Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Xutong Sun
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | | | - Qing Lu
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Evgeny Zemskov
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Ting Wang
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Saurabh Aggarwal
- Department of Anesthesiology, The University of Alabama, Birmingham, AL, United States
| | - Christine Gross
- Vascular Biology Center and the Center for Biotechnology & Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Shruti Sharma
- Center for Biotechnology & Genomic Medicine, Old Dominion University, Norfolk, VA, United States
| | - Ankit A Desai
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Yali Hou
- Vascular Biology Center and the Center for Biotechnology & Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Sridevi Dasarathy
- Vascular Biology Center and the Center for Biotechnology & Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Ning Qu
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Vijay Reddy
- Vascular Biology Center and the Center for Biotechnology & Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Sung Gon Lee
- Vascular Biology Center and the Center for Biotechnology & Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Mary Cherian-Shaw
- Vascular Biology Center and the Center for Biotechnology & Genomic Medicine, Augusta University, Augusta, GA, United States
| | - Jason X-J Yuan
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - John D Catravas
- Center for Biotechnology & Genomic Medicine, Old Dominion University, Norfolk, VA, United States
| | - Ruslan Rafikov
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Joe G N Garcia
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Stephen M Black
- Department of Medicine, The University of Arizona, Tucson, AZ, United States.
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21
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Gilinsky MA, Johnston TP, Zhukova NA, Dubrovina NI, Latysheva TV, Naumenko SE, Sukhovershin RA. Methylated arginine analogues: their potential role in atherosclerosis and cognition using the poloxamer-407-induced mouse model of dyslipidemia. Can J Physiol Pharmacol 2016; 94:1122-1131. [PMID: 27454106 DOI: 10.1139/cjpp-2016-0104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
An experimental mouse model of dyslipidemia and atherosclerosis was utilized to study the generation of methylarginines in vivo, as well as any potential behavioral changes in mice associated with the production of excess methylarginines. Following 14 weeks of poloxamer 407 treatment, mice developed atherosclerosis and the plasma concentrations of monomethylarginine and asymmetric dimethylarginine were found to be significantly greater than corresponding concentrations in control mice. This finding may have contributed to the development of aortic atherosclerotic lesions in poloxamer-treated mice by interfering with nitric oxide availability and, hence, normal function of vascular endothelium. Poloxamer-407-treated mice also showed a significant decrease in locomotor and exploratory activity, together with signs of emotional stress and anxiety relative to controls. Passive avoidance testing to assess learning and memory provided suggestive evidence that poloxamer-treated mice could potentially be characterized as having undergone a disruption in the process of forgetting about an aversive event, specifically, a foot shock, when compared with control mice. Thus, it is also suggested that the increase in both plasma monomethylarginine and asymmetric dimethylarginine in poloxamer-407-treated mice may somehow influence learning and memory, because endothelial dysfunction caused by reduced nitric oxide availability has been hypothesized to negatively influence cognitive function.
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Affiliation(s)
- Michael A Gilinsky
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
| | - Thomas P Johnston
- b Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108-2718, USA
| | - Natalia A Zhukova
- c Voroztzov N.N. Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Prosp. Acad. Lavrentjev, 630090, Novosibirsk, Russian Federation
| | - Nina I Dubrovina
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
| | - Tatyana V Latysheva
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
| | - Sergey E Naumenko
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
| | - Roman A Sukhovershin
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
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22
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PIŤHA J, KRÁLOVÁ LESNÁ I, STÁVEK P, MAHROVÁ A, RACEK J, SEKERKOVÁ A, TEPLAN V, ŠTOLLOVÁ M. Effect of Exercise on Markers of Vascular Health in Renal Transplant Recipients. Physiol Res 2015; 64:945-9. [DOI: 10.33549/physiolres.933123] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The cornerstone of cardiovascular risk management is lifestyle intervention including exercise which could exert favorable impact also in renal transplant recipients. Nevertheless, reliable assessment of the effect of lifestyle interventions is complicated and the available data in this population are not consistent. The aim of the study was to evaluate the effect of physical activity on selected laboratory markers of vascular health including circulating stem cells, endothelial progenitor cells, microparticles, and plasma asymmetric dimethyl arginine in renal transplant recipients. Nineteen men and 7 women were recruited in 6-month program of standardized and supervised exercise. Control group consisted of 23 men and 13 women of similar age and body mass index not included into the program. One year after the transplantation, the main difference between intervention and control group was found in the change of endothelial progenitor cells (p=0.006). Surprisingly, more favorable change was seen in the control group in which endothelial progenitor cells significantly increased compared to the intervention group. The explanation of this finding might be a chronic activation of reparative mechanisms of vascular system in the population exposed to multiple risk factors which is expressed as relatively increased number of endothelial progenitor cells. Therefore, their decrease induced by exercise might reflect stabilization of these processes.
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Affiliation(s)
- J. PIŤHA
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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23
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Austdal M, Tangerås LH, Skråstad RB, Salvesen K, Austgulen R, Iversen AC, Bathen TF. First Trimester Urine and Serum Metabolomics for Prediction of Preeclampsia and Gestational Hypertension: A Prospective Screening Study. Int J Mol Sci 2015; 16:21520-38. [PMID: 26370975 PMCID: PMC4613265 DOI: 10.3390/ijms160921520] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/17/2015] [Accepted: 08/26/2015] [Indexed: 01/03/2023] Open
Abstract
Hypertensive disorders of pregnancy, including preeclampsia, are major contributors to maternal morbidity. The goal of this study was to evaluate the potential of metabolomics to predict preeclampsia and gestational hypertension from urine and serum samples in early pregnancy, and elucidate the metabolic changes related to the diseases. Metabolic profiles were obtained by nuclear magnetic resonance spectroscopy of serum and urine samples from 599 women at medium to high risk of preeclampsia (nulliparous or previous preeclampsia/gestational hypertension). Preeclampsia developed in 26 (4.3%) and gestational hypertension in 21 (3.5%) women. Multivariate analyses of the metabolic profiles were performed to establish prediction models for the hypertensive disorders individually and combined. Urinary metabolomic profiles predicted preeclampsia and gestational hypertension at 51.3% and 40% sensitivity, respectively, at 10% false positive rate, with hippurate as the most important metabolite for the prediction. Serum metabolomic profiles predicted preeclampsia and gestational hypertension at 15% and 33% sensitivity, respectively, with increased lipid levels and an atherogenic lipid profile as most important for the prediction. Combining maternal characteristics with the urinary hippurate/creatinine level improved the prediction rates of preeclampsia in a logistic regression model. The study indicates a potential future role of clinical importance for metabolomic analysis of urine in prediction of preeclampsia.
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Affiliation(s)
- Marie Austdal
- Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
- St. Olavs Hospital, Trondheim University Hospital, 7006 Trondheim, Norway.
| | - Line H Tangerås
- St. Olavs Hospital, Trondheim University Hospital, 7006 Trondheim, Norway.
- Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
| | - Ragnhild B Skråstad
- Department of Laboratory Medicine Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
- National Center for Fetal Medicine, Department of Obstetrics and Gynecology, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway.
| | - Kjell Salvesen
- National Center for Fetal Medicine, Department of Obstetrics and Gynecology, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway.
- Department of Obstetrics and Gynecology, Clinical Sciences, Lund University, 221 00 Lund, Sweden.
| | - Rigmor Austgulen
- Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
| | - Ann-Charlotte Iversen
- Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
| | - Tone F Bathen
- Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
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Schultz CD, Rangneker G, Lim HS, Fraudeau A, Young G, Roberts-Thomson K, John B, Worthley M, Sanders P, Willoughby SR. Characterization of thrombogenic, endothelial and inflammatory markers in supraventricular tachycardia: a study in patients with structurally normal hearts. Clin Exp Pharmacol Physiol 2015; 41:551-7. [PMID: 24827644 DOI: 10.1111/1440-1681.12256] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 05/01/2014] [Accepted: 05/05/2014] [Indexed: 11/28/2022]
Abstract
Patients with atrial fibrillation (AF) are at an increased risk of thromboembolism and stroke primarily from the development of thrombi within the left atrium. Pathological changes in blood constituents and atrial endothelial damage promote left atrial thrombus formation. It is not known whether factors predisposing to left atrial thrombus formation in AF are disease specific or also evident within the normal heart. The present study examined whether there are differences in platelet reactivity, endothelial function and inflammation in blood samples obtained from intracardiac and peripheral sites in subjects within structurally normal hearts. Sixteen patients with diagnosed left-sided supraventricular tachycardia (SVT) undergoing a routine elective electrophysiological study and ablation were investigated. Blood samples were taken simultaneously from the femoral vein, right atrium and left atrium, immediately following trans-septal puncture and prior to heparin bolus administration. Between peripheral and atrial sample sites, patients with SVT showed no change in platelet reactivity or aggregation (P-selectin (CD62P) P = 0.91; platelet-derived soluble CD40 ligand P = 0.9), thrombus formation (thrombin-antithrombin complex; P = 0.55), endothelial function (von Willebrand factor P = 0.75; asymmetric dimethylarginine (ADMA) P = 0.97; nitric oxide P = 0.61), or inflammation (vascular cell adhesion molecule-1 P = 0.59; intercellular adhesion molecule-1 (ICAM-1) P = 0.69). However, SVT patients had lower ADMA and ICAM-1 levels than AF patients. The present study demonstrates, for the first time, that SVT subjects with structurally normal hearts have consistent haemostatic function between atrial and peripheral sites. These results suggest that the atria of SVT patients do not contain predisposing thrombogenic, endothelial or inflammatory factors that promote and/or initiate thrombus formation.
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Affiliation(s)
- Carlee D Schultz
- Centre for Heart Rhythm Disorders, University of Adelaide and Cardiovascular Investigation Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
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Reyna-Villasmil E, Mejia-Montilla J, Reyna-Villasmil N, Torres-Cepeda D, J.Santos-Bolívar, Aragón-Charry J. Concentraciones de dimetilarginina asimétrica en pacientes con preeclampsia y gestantes normotensas sanas. CLINICA E INVESTIGACION EN GINECOLOGIA Y OBSTETRICIA 2015. [DOI: 10.1016/j.gine.2013.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Xia W, Li D, Zhang C, Xu L, Xu W, Shao Y. Asymmetric dimethylarginine is associated with high-sensitivity C-reactive protein and early carotid atherosclerosis in women with previous gestational diabetes mellitus. Endocrine 2015; 48:528-32. [PMID: 24962795 DOI: 10.1007/s12020-014-0330-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Accepted: 06/05/2014] [Indexed: 12/22/2022]
Abstract
Asymmetric dimethylarginine (ADMA) is increased in subjects with previous gestational diabetes mellitus (GDM). The aim of this study was to investigate the relationship between serum ADMA levels and early carotid atherosclerosis in women with history of GDM. A total of 42 normoglycemic women with previous GDM and 42 age-matched healthy controls were enrolled. Serum levels of ADMA, lipids, insulin, fasting and 2-h glucose following 75-g oral glucose tolerance test, and high sensitivity C-reactive protein (hsCRP) were measured. Carotid atherosclerosis was evaluated by ultrasonographically determined intima-media thickness (IMT). Serum ADMA and hsCRP were higher in women with previous GDM compared to the healthy controls (0.72 ± 0.16 vs. 0.41 ± 0.15 μmol/L, p < 0.001; 1.81 ± 0.32 vs. 1.05 ± 0.26 mg/L, p < 0.001; respectively). Carotid IMT was also increased in the previous GDM group (0.77 ± 0.14 vs. 0.52 ± 0.13 mm, p < 0.001). In women with previous GDM, ADMA was positively correlated with hsCRP (r = 41, p < 0.001) and carotid IMT (r = 0.38, p < 0.001). Multiple linear regression analysis revealed that ADMA was a significant predictor for elevated carotid IMT in subjects with previous GDM after adjusting for traditional risk factors (β = 0.26, p = 0.017). Our data demonstrated that serum ADMA was associated with hsCRP and carotid IMT in normoglycemic women with previous GDM.
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Affiliation(s)
- Wei Xia
- Department of Cardiology, Qingdao Municipal Hospital, 5 Donghai Middle Road, Qingdao, 266071, Shandong, China
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Pinna A, Zinellu A, Tendas D, Blasetti F, Carru C, Castiglia P. Plasma Homocysteine and Asymmetrical Dimethyl-l-Arginine (ADMA) and Whole Blood DNA Methylation in Early and Neovascular Age-Related Macular Degeneration: A Pilot Study. Curr Eye Res 2015; 41:88-96. [PMID: 25611924 DOI: 10.3109/02713683.2014.1002044] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
PURPOSE/AIM To compare the plasma levels of homocysteine and asymmetrical dimethyl-l-arginine (ADMA) and the degree of whole blood DNA methylation in patients with early and neovascular age-related macular degeneration (AMD) and in controls without maculopathy of any sort. MATERIALS AND METHODS This observational case-control pilot study included 39 early AMD patients, 27 neovascular AMD patients and 132 sex- and age-matched controls without maculopathy. Plasma homocysteine and ADMA concentrations and the degree of whole blood DNA methylation were measured. Quantitative variables were compared by Student's t-test or Mann-Whitney test. Logistic regression models were used to investigate the significance of the association between early or wet AMD and some variables. RESULTS There were no significant differences in mean plasma homocysteine and ADMA concentrations and in the degree of whole blood DNA methylation between patients with early or neovascular AMD and their controls. Similarly, logistic regression analysis disclosed that plasma homocysteine and ADMA levels were not associated with an increased risk for early or neovascular AMD. CONCLUSIONS We failed to demonstrate an association between early or neovascular AMD and increased plasma homocysteine and/or ADMA. Results also suggest that the degree of whole blood DNA methylation is not a marker of AMD.
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Affiliation(s)
- Antonio Pinna
- a Department of Surgical , Microsurgical, and Medical Sciences, Section of Ophthalmology, University of Sassari , Sassari , Italy .,b Azienda Ospedaliero-Universitaria di Sassari , Sassari , Italy
| | - Angelo Zinellu
- c Department of Biomedical Sciences , Section of Clinical Biochemistry, University of Sassari , Sassari , Italy and
| | - Donatella Tendas
- a Department of Surgical , Microsurgical, and Medical Sciences, Section of Ophthalmology, University of Sassari , Sassari , Italy
| | - Francesco Blasetti
- a Department of Surgical , Microsurgical, and Medical Sciences, Section of Ophthalmology, University of Sassari , Sassari , Italy
| | - Ciriaco Carru
- b Azienda Ospedaliero-Universitaria di Sassari , Sassari , Italy .,c Department of Biomedical Sciences , Section of Clinical Biochemistry, University of Sassari , Sassari , Italy and
| | - Paolo Castiglia
- b Azienda Ospedaliero-Universitaria di Sassari , Sassari , Italy .,d Department of Biomedical Sciences, Laboratory of Epidemiology and Biostatistics , University of Sassari , Sassari , Italy
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28
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Symmetric dimethylarginine alters endothelial nitric oxide activity in glomerular endothelial cells. Cell Signal 2015; 27:1-5. [DOI: 10.1016/j.cellsig.2014.09.024] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 09/02/2014] [Accepted: 09/23/2014] [Indexed: 01/27/2023]
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Aggarwal S, Gross CM, Kumar S, Dimitropoulou C, Sharma S, Gorshkov BA, Sridhar S, Lu Q, Bogatcheva NV, Jezierska-Drutel AJ, Lucas R, Verin AD, Catravas JD, Black SM. Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury. Am J Respir Cell Mol Biol 2014; 50:614-25. [PMID: 24134589 DOI: 10.1165/rcmb.2013-0193oc] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Acute lung injury (ALI) is a severe hypoxemic respiratory insufficiency associated with lung leak, diffuse alveolar damage, inflammation, and loss of lung function. Decreased dimethylaminohydrolase (DDAH) activity and increases in asymmetric dimethylarginine (ADMA), together with exaggerated oxidative/nitrative stress, contributes to the development of ALI in mice exposed to LPS. Whether restoring DDAH function and suppressing ADMA levels can effectively ameliorate vascular hyperpermeability and lung injury in ALI is unknown, and was the focus of this study. In human lung microvascular endothelial cells, DDAH II overexpression prevented the LPS-dependent increase in ADMA, superoxide, peroxynitrite, and protein nitration. DDAH II also attenuated the endothelial barrier disruption associated with LPS exposure. Similarly, in vivo, we demonstrated that the targeted overexpression of DDAH II in the pulmonary vasculature significantly inhibited the accumulation of ADMA and the subsequent increase in oxidative/nitrative stress in the lungs of mice exposed to LPS. In addition, augmenting pulmonary DDAH II activity before LPS exposure reduced lung vascular leak and lung injury and restored lung function when DDAH activity was increased after injury. Together, these data suggest that enhancing DDAH II activity may prove a useful adjuvant therapy to treat patients with ALI.
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Affiliation(s)
- Saurabh Aggarwal
- Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia
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30
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Wahlström MR, Olivecrona M, Ahlm C, Bengtsson A, Koskinen LOD, Naredi S, Hultin M. Effects of prostacyclin on the early inflammatory response in patients with traumatic brain injury-a randomised clinical study. SPRINGERPLUS 2014; 3:98. [PMID: 24600548 PMCID: PMC3942562 DOI: 10.1186/2193-1801-3-98] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 02/13/2014] [Indexed: 01/05/2023]
Abstract
OBJECTIVE AND DESIGN A prospective, randomised, double-blinded, clinical trial was performed at a level 1 trauma centre to determine if a prostacyclin analogue, epoprostenol (Flolan®), could attenuate systemic inflammatory response in patients with severe traumatic brain injury (TBI). SUBJECTS 46 patients with severe TBI, randomised to epoprostenol (n = 23) or placebo (n = 23). TREATMENT Epoprostenol, 0.5 ng · kg(-1) · min(-1), or placebo (saline) was given intravenously for 72 hours and then tapered off over the next 24 hours. METHODS Interleukin-6 (IL-6), interleukin-8 (IL-8), soluble intracellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP), and asymmetric dimethylarginine (ADMA) levels were measured over five days. Measurements were made at 24 h intervals ≤24 h after TBI to 97-120 h after TBI. RESULTS A significantly lower CRP level was detected in the epoprostenol group compared to the placebo group within 73-96 h (p = 0.04) and within 97-120 h (p = 0.008) after trauma. IL-6 within 73-96 h after TBI was significantly lower in the epoprostenol group compared to the placebo group (p = 0.04). ADMA was significantly increased within 49-72 h and remained elevated, but there was no effect of epoprostenol on ADMA levels. No significant differences between the epoprostenol and placebo groups were detected for IL-8 or sICAM-1. CONCLUSIONS Administration of the prostacyclin analogue epoprostenol significantly decreased CRP and, to some extent, IL-6 levels in patients with severe TBI compared to placebo. These findings indicate an interesting option for treatment of TBI and warrants future larger studies. TRIAL REGISTRATION ClinicalTrials.gov Identifier, NCT01363583.
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Affiliation(s)
- Marie Rodling Wahlström
- Department of Surgical and Perioperative Sciences, Anaesthesiology and Intensive Care, Umeå University, S-901 87 Umeå, Sweden
| | - Magnus Olivecrona
- Department of Pharmacology and Clinical Neurosciences, Neurosurgery, Umeå University, S-901 87 Umeå, Sweden
| | - Clas Ahlm
- Department of Clinical Microbiology, Infectious Diseases, Umeå University, S-901 87 Umeå, Sweden
| | - Anders Bengtsson
- Institute of Clinical Sciences, Department of Anesthesiology and Intensive Care, The Sahlgrenska Academy, University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Lars-Owe D Koskinen
- Department of Pharmacology and Clinical Neurosciences, Neurosurgery, Umeå University, S-901 87 Umeå, Sweden
| | - Silvana Naredi
- Department of Surgical and Perioperative Sciences, Anaesthesiology and Intensive Care, Umeå University, S-901 87 Umeå, Sweden
| | - Magnus Hultin
- Department of Surgical and Perioperative Sciences, Anaesthesiology and Intensive Care, Umeå University, S-901 87 Umeå, Sweden
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Schulz E, Wenzel P, Münzel T, Daiber A. Mitochondrial redox signaling: Interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid Redox Signal 2014; 20:308-24. [PMID: 22657349 PMCID: PMC3887453 DOI: 10.1089/ars.2012.4609] [Citation(s) in RCA: 189] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
SIGNIFICANCE Oxidative stress is a well established hallmark of cardiovascular disease and there is strong evidence for a causal role of reactive oxygen and nitrogen species (RONS) therein. RECENT ADVANCES Improvement of cardiovascular complications by genetic deletion of RONS producing enzymes and overexpression of RONS degrading enzymes proved the involvement of these species in cardiovascular disease at a molecular level. Vice versa, overexpression of RONS producing enzymes as well as deletion of antioxidant enzymes was demonstrated to aggravate cardiovascular complications. CRITICAL ISSUES With the present overview we present and discuss different pathways how mitochondrial RONS interact (crosstalk) with other sources of oxidative stress, namely NADPH oxidases, xanthine oxidase and an uncoupled nitric oxide synthase. The potential mechanisms of how this crosstalk proceeds are discussed in detail. Several examples from the literature are summarized (including hypoxia, angiotensin II mediated vascular dysfunction, cellular starvation, nitrate tolerance, aging, hyperglycemia, β-amyloid stress and others) and the underlying mechanisms are put together to a more general concept of redox-based activation of different sources of RONS via enzyme-specific "redox switches". Mitochondria play a key role in this concept providing redox triggers for oxidative damage in the cardiovascular system but also act as amplifiers to increase the burden of oxidative stress. FUTURE DIRECTIONS Based on these considerations, the characterization of the role of mitochondrial RONS formation in cardiac disease as well as inflammatory processes but also the role of mitochondria as potential therapeutic targets in these pathophysiological states should be addressed in more detail in the future.
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Affiliation(s)
- Eberhard Schulz
- 1 2nd Medical Clinic, Molecular Cardiology, Medical Center of the Johannes Gutenberg University , Mainz, Germany
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32
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Lindgren C, Hultin M, Koskinen LOD, Lindvall P, Borota L, Naredi S. ADMA Levels and Arginine/ADMA Ratios Reflect Severity of Disease and Extent of Inflammation After Subarachnoid Hemorrhage. Neurocrit Care 2014; 21:91-101. [DOI: 10.1007/s12028-013-9945-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Gürel E, Tigen K, Karaahmet T, Geçmen Ç, Mutlu B, Başaran Y. Predictive value of plasma asymmetric dimethylarginine, homocysteine, and high-sensitive CRP levels in occult coronary artery disease. Herz 2013; 40:495-501. [DOI: 10.1007/s00059-013-4022-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 10/21/2013] [Accepted: 11/02/2013] [Indexed: 11/28/2022]
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Rochette L, Lorin J, Zeller M, Guilland JC, Lorgis L, Cottin Y, Vergely C. Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: Possible therapeutic targets? Pharmacol Ther 2013; 140:239-57. [DOI: 10.1016/j.pharmthera.2013.07.004] [Citation(s) in RCA: 269] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 06/14/2013] [Indexed: 12/14/2022]
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Sozer V, Uzun H, Gelisgen R, Kaya M, Kalayci R, Tabak O, Arican N, Konukoglu D. The effects of atorvastatin on oxidative stress in L-NAME-treated rats. Scandinavian Journal of Clinical and Laboratory Investigation 2013; 73:591-7. [PMID: 24024670 DOI: 10.3109/00365513.2013.828241] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Current evidence suggests that the beneficial vascular effects of statins are not limited to the statins' lipid-lowering properties; these drugs can also improve vascular endothelial cell function. Nω-nitro-l-arginine methyl ester (L-NAME) is a potent synthetic nitric oxide inhibitor, and long-term oral L-NAME treatment is used to induce vascular lesions in experimental animal models. METHODS We determined the effects of statins on protein carbonyl (PCO), lipid hydroperoxides (LHP), oxidized low-density lipoproteins (ox-LDL) and antioxidants such as paraoxonase 1 (PON1) and total thiols (T-SH) in long-term L-NAME-treated rats. Adult male Wistar rats were divided into three groups, namely, control, L-NAME-treated (1 mg/mL in drinking water for three weeks), and atorvastatin plus L-NAME-treated (4 mg/kg/day atorvastatin for 1 week during the third week of L-NAME treatment) groups. RESULTS In the L-NAME group, the ox-LDL, LHP and PCO were higher and the PON1 and T-SH were lower than the concentrations observed for the controls. When compared with the L-NAME group, the L-NAME plus atorvastatin group had significantly lower ox-LDL and LHP and higher PON1 activities. Additionally, the elevated total cholesterol (TC) and low-density lipoprotein-C (LDL-C) in the L-NAME group were decreased by atorvastatin administration. TC and LDL-C were positively correlated with ox-LDL and LHP and negatively correlated with PON1 in all groups. High-density lipoprotein-C (HDL-C) was negatively correlated with ox-LDL. CONCLUSION PON1 prevents LDL oxidation and inactivates LDL-derived oxidized phospholipids; its activity showed a pronounced decrease in the L-NAME treatment group and was increased in the atorvastatin group. Based on our findings, we concluded that the atorvastatin had HDL-related antioxidant activity as well as lipid-lowering properties.
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Affiliation(s)
- Volkan Sozer
- Department of Biochemistry, Yildiz Technical University , Istanbul
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Osorio-Yáñez C, Ayllon-Vergara JC, Aguilar-Madrid G, Arreola-Mendoza L, Hernández-Castellanos E, Barrera-Hernández A, De Vizcaya-Ruiz A, Del Razo LM. Carotid intima-media thickness and plasma asymmetric dimethylarginine in Mexican children exposed to inorganic arsenic. ENVIRONMENTAL HEALTH PERSPECTIVES 2013; 121:1090-6. [PMID: 23757599 PMCID: PMC3764073 DOI: 10.1289/ehp.1205994] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2012] [Accepted: 06/07/2013] [Indexed: 05/02/2023]
Abstract
BACKGROUND Arsenic exposure is a risk factor for atherosclerosis in adults, but there is little information on arsenic and early risk biomarkers for atherosclerosis in children. Carotid intima-media thickness (cIMT) is an indicator of subclinical atherosclerotic burden that has been associated with plasma asymmetric dimethylarginine (ADMA), a predictor of cardiovascular disease risk. OBJECTIVES The aim of this study was to investigate associations of arsenic exposure with cIMT, ADMA, and endothelial adhesion molecules [soluble intercellular cell adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1)] in children who had been exposed to environmental inorganic arsenic (iAs). METHODS We conducted a cross-sectional study in 199 children 3-14 years of age who were residents of Zimapan, México. We evaluated cIMT using ultrasonography, and plasma lipid profiles by standard methods. We analyzed ADMA, sICAM-1, and sVCAM-1 by ELISA, and measured the concentrations of total speciated arsenic (tAs) in urine using hydride generation cryotrapping atomic absorption spectrometry. RESULTS In the multiple linear regression model for cIMT, tAs categories were positively associated with cIMT increase. The estimated cIMT diameter was greater in 35- to 70-ng/mL and > 70-ng/mL groups (0.035 mm and 0.058 mm per 1-ng/mL increase in urinary tAs, respectively), compared with the < 35-ng/mL group. In addition to tAs level, plasma ADMA was a significant predictor of cIMT. In the adjusted regression model, cIMT, percent iAs, and plasma sVCAM-1 were significant predictors of ADMA levels (e.g., 0.419-μmol/L increase in ADMA per 1-mm increase in cIMT). CONCLUSIONS Arsenic exposure and plasma ADMA levels were positively associated with cIMT in a population of Mexican children with environmental arsenic exposure through drinking water.
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Affiliation(s)
- Citlalli Osorio-Yáñez
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México
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Mikropoulos DG, Mallini P, Michopoulou A, Giannopoulos T, Arranz-Marquez E, Koliakos GG, Konstas AGP. Asymmetric Dimethyloarginin (ADMA) Concentration in the Aqueous Humor of Patients with Exfoliation Syndrome or Exfoliative Glaucoma. Curr Eye Res 2013; 38:266-70. [DOI: 10.3109/02713683.2012.757325] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Noh JS, Choi YH, Song YO. Beneficial effects of the active principle component of Korean cabbage kimchi via increasing nitric oxide production and suppressing inflammation in the aorta of apoE knockout mice. Br J Nutr 2013; 109:17-24. [PMID: 22715945 DOI: 10.1017/s0007114512000633] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The present study investigated the effects of 3'-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), the active principle compound of kimchi, on vascular damage in the experimental atherosclerotic animal. HDMPPA was administrated by an intraperitoneal injection of 10 mg/kg per d for 8 weeks to apoE knockout (KO) mice with an atherogenic diet containing 1 % cholesterol, and its effects were compared with vehicle-treated control mice. HDMPPA increased NO content in the aorta, accompanied by a decrease in reactive oxygen species (ROS) concentration. Furthermore, in the HDMPPA-treated group, aortic endothelial NO synthase (eNOS) expression was up-regulated compared with the control group. These results suggested that HDMPPA could maintain NO bioavailability through an increasing eNOS expression and preventing NO degradation by ROS. Furthermore, HDMPPA treatment in apoE KO mice inhibited eNOS uncoupling through an increase in vascular tetrahydrobiopterin content and a decrease in serum asymmetric dimethylarginine levels. Moreover, HDMPPA ameliorates inflammatory-related protein expression in the aorta of apoE KO mice. Therefore, the present study suggests that HDMPPA, the active compound of kimchi, a Korean functional food, may exert its vascular protective effect through the preservation of NO bioavailability and suppression of the inflammatory response.
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Affiliation(s)
- Jeong Sook Noh
- Department of Food Science and Nutrition, Kimchi Research Institute, Pusan National University, Busan 609-735, Republic of Korea
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Vaspin increases nitric oxide bioavailability through the reduction of asymmetric dimethylarginine in vascular endothelial cells. PLoS One 2012; 7:e52346. [PMID: 23284999 PMCID: PMC3532208 DOI: 10.1371/journal.pone.0052346] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Accepted: 11/12/2012] [Indexed: 11/19/2022] Open
Abstract
Vaspin is an adipocytokine recently identified in the visceral adipose tissue of diabetic rats and having anti-diabetic effects. We have recently shown that vaspin has anti-atherogenic effect through Akt-mediated inhibition of endothelial cell apoptosis. Decreased activity of endothelial nitric oxide synthase (eNOS) plays an important role in the pathogenesis of atherosclerosis. Asymmetric dimethylarginine (ADMA) is a well-known endogenous competitive inhibitor of eNOS and risk factor of cardiovascular diseases. The aim of this study was to examine whether vaspin might protect against atherosclerosis through its beneficial effects on the ADMA-eNOS system. Treatment of vaspin significantly increased NO secretion from endothelial cells and isolated aorta from Sprague-Dawley (SD) rats. Furthermore, treatment of vaspin prevented fatty acid-induced decrease in endothelium-dependent vasorelaxation in isolated aorta of SD rat. For the mechanism of vaspin-induced NO biosynthesis, vaspin activated the STAT3 signaling pathway and stimulated eNOS phosphorylation (Ser 1177), a marker of eNOS activation, through STAT3-dependent mechanism. Furthermore, vaspin treatment increased the expression of dimethylarginine dimethylaminohydrolase (DDAH) II, the responsible enzyme for the degradation of ADMA, leading to a reduction in ADMA levels. Vaspin-induced increase in DDAH II gene expression was through STAT3-mediated stimulation of DDAH II promoter activity. These results suggest that vaspin increases eNOS activity by reducing ADMA level through STAT3-mediated regulation of DDAH II expression. Our findings provide a novel molecular mechanism of antiatherogenic actions of vaspin.
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Choi YS, Yang HI, Cho S, Jung JA, Jeon YE, Kim HY, Seo SK, Lee BS. Serum asymmetric dimethylarginine, apelin, and tumor necrosis factor-α levels in non-obese women with polycystic ovary syndrome. Steroids 2012; 77:1352-8. [PMID: 22944040 DOI: 10.1016/j.steroids.2012.08.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2011] [Revised: 05/28/2012] [Accepted: 08/09/2012] [Indexed: 10/27/2022]
Abstract
Polycystic ovary syndrome (PCOS) is associated with multiple risk factors for cardiovascular disease (CVD), including insulin resistance, type 2 diabetes mellitus, obesity, hypertension, and dyslipidemia. In addition, hyperandrogenism may contribute to the pathogenesis of CVD, independent of obesity and insulin resistance. We investigated serum levels of asymmetric dimethylarginine (ADMA), apelin, and tumor necrosis factor (TNF)-α as CVD risk markers and their relationship with hyperandrogenism in non-obese women with PCOS. In this study were included 82 non-obese women with PCOS and 33 controls. Women with PCOS were further divided into two groups: women with hyperandrogenism (HA-PCOS, n=37) and those without hyperandrogenism (NA-PCOS, n=45). Serum ADMA, apelin, and TNF-α levels were compared among the three groups and their relationship with hyperandrogenism was evaluated. Serum ADMA levels were significantly higher in the HA-PCOS group than in the NA-PCOS and control groups (0.45 ± 0.09 vs. 0.38 ± 0.08 vs. 0.40 ± 0.07; P<0.0005). Serum TNF-α levels were significantly higher among women with PCOS compared with controls (2.91 ± 1.25 vs. 1.74 ± 0.77; P<0.001) and in the HA-PCOS group compared with the NA-PCOS group (3.21 ± 1.24 vs. 2.60 ± 1.24; P<0.0001). Both PCOS groups had significantly lower serum apelin levels compared with controls (1.31 ± 0.54 vs. 1.16 ± 0.34 vs. 2.78 ± 1.10; P<0.0001). ADMA and TNF-α were positively correlated with total testosterone (r=0.219, P=0.022; r=0.332, P<0.001, respectively) and free androgen index (r=0.287, P=0.002; r=0.289, P=0.002, respectively), whereas apelin was negatively correlated with these parameters (r=-0.362, P<0.001; r=-0.251, P=0.008). These findings may indicate that non-obese women with PCOS are at an increased risk for CVD, which is further aggravated by hyperandrogenism.
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Affiliation(s)
- Young Sik Choi
- Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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Improving Total-Cholesterol/HDL-Cholesterol Ratio Results in an Endothelial Dysfunction Recovery in Peripheral Artery Disease Patients. CHOLESTEROL 2012; 2012:895326. [PMID: 23050131 PMCID: PMC3463157 DOI: 10.1155/2012/895326] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Accepted: 08/22/2012] [Indexed: 01/08/2023]
Abstract
Aims. To evaluate the effects of variations of total-cholesterol/HDL-cholesterol ratio and the effects of the atorvastatin on endothelial function in peripheral artery disease (PAD). Material and Methods. A prospective, randomised controlled study was carried out in 150 PAD patients. Patients randomized to the control group (n = 75) were treated with antiplatelet drugs, angiotensin-converting-enzyme inhibitors and cardiovascular-risk-factor control. Experimental group (n = 75) also received treatment with atorvastatin for a month. It was determined baseline nitrite plasma levels and total-cholesterol/HDL-cholesterol ratio and after one month of treatment in both groups. It was also analysed the correlation between the gradient of nitrite levels and the differential of total-cholesterol/HDL ratio in treatment group. Results. After a month, a reduction in nitrite levels was detected in treatment group (11.88 ± 7.8 μM versus 5.7 ± 1.8 μM, P < 0.0001). It was shown a higher decrease in nitrite plasma levels in the atorvastatin group finding lower levels assessments (5.7 ± 1.8 μM versus 13.1 ± 9.1 μM, resp., P < 0.001). A significant reduction in total-cholesterol/HDL-cholesterol ratio was observed in statin group after treatment (P < 0.0001). A strong correlation was found between the gradient of nitrite levels and the differential of total-cholesterol/HDL-cholesterol ratio in atorvastatin group (r = 0.7; P < 0.001). Conclusions. Improvement of nitrite levels are associated with decreased total cholesterol/HDL ratio values in PAD patients treated with atorvastatin.
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Vassiliadis E, Barascuk N, Didangelos A, Karsdal MA. Novel cardiac-specific biomarkers and the cardiovascular continuum. Biomark Insights 2012; 7:45-57. [PMID: 22577298 PMCID: PMC3347891 DOI: 10.4137/bmi.s9536] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The concept of the cardiovascular continuum, introduced during the early 1990s, created a holistic view of the chain of events connecting cardiovascular-related risk factors with the progressive development of pathological-related tissue remodelling and ultimately, heart failure and death. Understanding of the tissue-specific changes, and new technologies developed over the last 25-30 years, enabled tissue remodelling events to be monitored in vivo and cardiovascular disease to be diagnosed more reliably than before. The tangible product of this evolution was the introduction of a number of biochemical markers such as troponin I and T, which are now commonly used in clinics to measure myocardial damage. However, biomarkers that can detect specific earlier stages of the cardiovascular continuum have yet to be generated and utilised. The majority of the existing markers are useful only in the end stages of the disease where few successful intervention options exist. Since a large number of patients experience a transient underlying developing pathology long before the signs or symptoms of cardiovascular disease become apparent, the requirement for new markers that can describe the early tissue-specific, matrix remodelling process which ultimately leads to disease is evident. This review highlights the importance of relating cardiac biochemical markers with specific time points along the cardiovascular continuum, especially during the early transient phase of pathology progression where none of the existing markers aid diagnosis.
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Affiliation(s)
- Efstathios Vassiliadis
- Nordic Bioscience A/S, Herlev, Denmark
- School of Endocrinology, University of Southern Denmark, Odense, Denmark
| | - Natasha Barascuk
- Nordic Bioscience A/S, Herlev, Denmark
- School of Endocrinology, University of Southern Denmark, Odense, Denmark
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The effect of simvastatin on asymmetric dimethylarginine and flow-mediated vasodilation after optimizing the LDL level — A randomized, placebo-controlled study. Vascul Pharmacol 2012; 56:122-30. [DOI: 10.1016/j.vph.2011.10.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2010] [Revised: 10/02/2011] [Accepted: 10/30/2011] [Indexed: 01/06/2023]
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Rizos D, Eleftheriades M, Batakis E, Rizou M, Haliassos A, Hassiakos D, Botsis D. Levels of asymmetric dimethylarginine throughout normal pregnancy and in pregnancies complicated with preeclampsia or had a small for gestational age baby. J Matern Fetal Neonatal Med 2011; 25:1311-5. [DOI: 10.3109/14767058.2011.632037] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Rueda‐Clausen CF, Córdoba‐Porras A, Bedoya G, Silva FA, Zarruk JG, López‐Jaramillo P, Villa LA. Increased plasma levels of total homocysteine but not asymmetric dimethylarginine in Hispanic subjects with ischemic stroke FREC‐VI sub‐study. Eur J Neurol 2011; 19:417-25. [DOI: 10.1111/j.1468-1331.2011.03534.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- C. F. Rueda‐Clausen
- Grupo de Ciencias Neurovasculares, Fundación Cardiovascular de Colombia, Bucaramanga
| | - A. Córdoba‐Porras
- Grupo Neuroendotelio y Enfermedad Cerebrovascular‐Facultad de Medicina‐Universidad de Antioquia, Medellín
| | - G. Bedoya
- Genética Molecular Sede de Investigación Universitaria Universidad de Antioquia, Medellín
| | - F. A. Silva
- Grupo de Ciencias Neurovasculares, Fundación Cardiovascular de Colombia, Bucaramanga
| | - J. G. Zarruk
- Grupo de Ciencias Neurovasculares, Fundación Cardiovascular de Colombia, Bucaramanga
| | - P. López‐Jaramillo
- Research Director, Fundación Oftalmológica de Santander‐FOSCAL, Bucaramanga
| | - L. A. Villa
- Grupo Neuroendotelio y Enfermedad Cerebrovascular‐Facultad de Medicina‐Universidad de Antioquia, Medellín
- Departamento de Medicina interna, Neurología‐Facultad de Medicina Universidad de Antioquia, Medellín, Colombia
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Sun X, Fratz S, Sharma S, Hou Y, Rafikov R, Kumar S, Rehmani I, Tian J, Smith A, Schreiber C, Reiser J, Naumann S, Haag S, Hess J, Catravas JD, Patterson C, Fineman JR, Black SM. C-terminus of heat shock protein 70-interacting protein-dependent GTP cyclohydrolase I degradation in lambs with increased pulmonary blood flow. Am J Respir Cell Mol Biol 2011; 45:163-71. [PMID: 20870896 PMCID: PMC3145069 DOI: 10.1165/rcmb.2009-0467oc] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2009] [Accepted: 08/13/2010] [Indexed: 12/30/2022] Open
Abstract
We showed that nitric oxide (NO) signaling is decreased in the pulmonary vasculature before the development of endothelial dysfunction in a lamb model of congenital heart disease and increased pulmonary blood flow (Shunt). The elucidation of the molecular mechanism by which this occurs was the purpose of this study. Here, we demonstrate that concentrations of the endogenous NO synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), are elevated, whereas the NOS cofactor tetrahydrobiopterin (BH(4)) is decreased in Shunt lambs. Our previous studies demonstrated that ADMA decreases heat shock protein-90 (Hsp90) chaperone activity, whereas other studies suggest that guanosine-5'-triphosphate cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the generation of BH(4), may be a client protein for Hsp90. Thus, we determined whether increases in ADMA could alter GCH1 protein and activity. Our data demonstrate that ADMA decreased GCH1 protein, but not mRNA concentrations, in pulmonary arterial endothelial cells (PAECs) because of the ubiquitination and proteasome-dependent degradation of GCH1. We also found that Hsp90-GCH1 interactions were reduced, whereas the association of GCH1 with Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) increased in ADMA-exposed PAECs. The overexpression of CHIP potentiated, whereas a CHIP U-box domain mutant attenuated, ADMA-induced GCH1 degradation and reductions in cellular BH(4) concentrations. We also found in vivo that Hsp90/GCH1 interactions are decreased, whereas GCH1-Hsp70 and GCH1-CHIP interactions and GCH1 ubiquitination are increased. Finally, we found that supplementation with l-arginine restored Hsp90-GCH1 interactions and increased both BH(4) and NO(x) concentrations in Shunt lambs. In conclusion, increased concentrations of ADMA can indirectly alter NO signaling through decreased cellular BH(4) concentrations, secondary to the disruption of Hsp90-GCH1 interactions and the CHIP-dependent proteasomal degradation of GCH1.
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Affiliation(s)
- Xutong Sun
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Sohrab Fratz
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Shruti Sharma
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Yali Hou
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Ruslan Rafikov
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Sanjiv Kumar
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Imran Rehmani
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Jing Tian
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Anita Smith
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Christian Schreiber
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Judith Reiser
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Susanne Naumann
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Sebastian Haag
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - John Hess
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - John D. Catravas
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Cam Patterson
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Jeffery R. Fineman
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
| | - Stephen M. Black
- Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; Section of Pediatric Cardiology and Congenital Heart Disease and Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany; Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California
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Zhang Q, Chen N, Qiu W, Xu X, Wang D, Tsao PS, Jin H. Asymmetric dimethylarginine impairs fibrinolytic activity in human umbilical vein endothelial cells via p38 MAPK and NF-κB pathways. Thromb Res 2011; 128:42-6. [PMID: 21429569 DOI: 10.1016/j.thromres.2011.02.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2010] [Revised: 02/18/2011] [Accepted: 02/20/2011] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Asymmetric dimethylarginine (ADMA) is a potent endogenous inhibitor of nitric oxide (NO) synthase. An increased synthesis and/or a reduced catabolism of ADMA might contribute to the onset and progression of thrombosis. The present study was designed to evaluate the effect of ADMA on fibrinolytic factors in endothelial cells, and to investigate the cellular mechanisms. MATERIALS AND METHODS Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of ADMA for various periods; Then HUVECs were preincubated with NO precursor (L-arginine), MAPK inhibitors, or NF-κB inhibitor (PDTC) before ADMA treatment to repeat the experiment. Protein levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), and NF-κB activity were measured by ELISA; mRNA levels of tPA and PAI-1 were assayed by qRT-PCR; The activation of MAPK was characterized by western blot analysis. RESULTS (1) ADMA decreased tPA antigen levels in time- and concentration-dependent manners, with the maximum effect of 30 μmol/L ADMA for 48h (control 109.01 ± 4.15 ng/ml vs ADMA 86.76 ± 5.95 ng/ml, p<0.01); (2) 30 μmol/L ADMA elevated antigen levels of PAI-1 in a time-dependent manner, with the maximum effect of 30 μmol/L ADMA for 48 h (control 2721.12 ± 278.02 ng/ml vs. ADMA 3435.78 ± 22.33ng/ml, p<0.05); (3) ADMA reduced tPA mRNA levels and increased PAI-1 mRNA levels; (4) L-arginine, SB203580 (p38 MAPK inhibitor) and PDTC attenuated the effects of ADMA on tPA and PAI-1 significantly. (5) ADMA induced a rapid phosphorylation of p38 MAPK, and stimulated NF-κB activity greatly. CONCLUSIONS ADMA may accelerate thrombosis development by impairing fibrinolytic activity in vascular via inhibiting nitric oxide production and then activating its downstream p38 MAPK and NF-κB pathways.
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Affiliation(s)
- Qin Zhang
- The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
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Peng ZY, Zhang SD, Liu S, He BM. Protective effect of neferine on endothelial cell nitric oxide production induced by lysophosphatidylcholine: the role of the DDAH–ADMA pathway. Can J Physiol Pharmacol 2011; 89:289-94. [PMID: 21526974 DOI: 10.1139/y11-021] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Neferine, extracted from the seed embryo of Nelumbo nucifera Gaertn., has multiple cardiovascular pharmacological effects. The dimethylarginine dimethylaminohydrolase (DDAH) – asymmetric dimethylarginine (ADMA) system is a novel pathway for modulating nitric oxide (NO) production. The aim of this study was to investigate whether the protective effect of neferine on endothelial NO production was related to the DDAH–ADMA pathway. Human umbilical vein endothelial cells (HUVECs) were first exposed to neferine (0.1, 1.0, or 10.0 μmol/L) for 1 h, and then incubated with lysophosphatidylcholine (LPC; 10 μg/mL) in the presence of neferine for 24 h. The medium was collected for measuring the levels of NO, maleic dialdehyde (MDA), as well as ADMA. The endothelial cells were collected for measuring DDAH activity and the level of reactive oxygen species (ROS). LPC significantly decreased NO concentration and DDAH activity and increased the levels of ADMA, ROS, and MDA. Neferine could partially counteract the changes induced by LPC. These findings suggested that neferine could modulate the DDAH–ADMA pathway via its antioxidant properties, which was involved in its beneficial effect on endothelial NO production.
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Affiliation(s)
- Zhen-Yu Peng
- Department of Cardiology, Xiangya Hospital, Central South University, Xiangya Road No. 88, Changsha, P.R. China
- Department of Emergency, Second Xiangya Hospital, Central South University, Middle Ren-Min Road No. 139, Changsha, P.R. China
| | - Sai-Dan Zhang
- Department of Cardiology, Xiangya Hospital, Central South University, Xiangya Road No. 88, Changsha, P.R. China
| | - Shao Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Xiangya Road No. 88, Changsha, P.R. China
| | - Bai-Mei He
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Xiangya Road No. 88, Changsha, P.R. China
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Zinellu A, Sotgia S, Porcu P, Casu MA, Bivona G, Chessa R, Deiana L, Carru C. Carotid restenosis is associated with plasma ADMA concentrations in carotid endarterectomy patients. Clin Chem Lab Med 2011; 49:897-901. [PMID: 21288172 DOI: 10.1515/cclm.2011.121] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The aim of this work has been to study the association between plasma asymmetric dimethylarginine (ADMA) concentrations and carotid stenosis in a group of 64 patients undergoing carotid endarterectomy (CEA). METHODS Arginine, ADMA and symmetric dimethylarginine (SDMA) were measured using capillary electrophoresis with UV detection. An evaluation of plasma concentrations of total cysteine (tCys) and total homocysteine (tHcy) was also performed. RESULTS Pearson's analysis show a positive correlation between ADMA and carotid stenosis (r=0.37, p=0.003), which is also confirmed after stepwise multiple linear regression analysis. ADMA plasma concentrations were significantly associated with tHcy (r=0.40, p=0.001) and to a lesser extent, even if not significantly, with tCys (r=0.23, p=0.07). CONCLUSIONS Our data suggest that plasma ADMA is involved in carotid narrowing after CEA intervention. This suggests that this molecule may have an important role in the events that lead to stenosis.
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Affiliation(s)
- Angelo Zinellu
- Department of Biomedical Sciences and Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari, Sassari, Italy.
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Peng ZY, Zhao SP, He BM, Peng DQ, Hu M. Protective effect of HDL on endothelial NO production: the role of DDAH/ADMA pathway. Mol Cell Biochem 2011; 351:243-9. [PMID: 21264497 DOI: 10.1007/s11010-011-0731-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Accepted: 01/10/2011] [Indexed: 12/01/2022]
Abstract
Accumulating studies have demonstrated that the dimethylarginine dimethylaminohydrolase/asymmetric dimethylarginine (DDAH/ADMA) system is a novel pathway for modulating nitric oxide (NO) production. The aim of this study was to investigate whether the protective effect of high density lipoprotein (HDL) on endothelial NO production was related to its effect on DDAH/ADMA pathway. Human umbilical vein endothelial cells (HUVECs) were prior exposed to HDL (10, 50, or 100 μg/ml) for 1 h, and then incubated with oxidized low density lipoprotein (ox-LDL) (100 μg/ml) for 24 h. The cultured medium was collected for measuring the concentration of NO and ADMA. The cells were collected for measuring the mRNA and protein expression of DDAH-II as well as DDAH activity. HUVECs treated with ox-LDL (100 μg/ml) for 24 h significantly decreased the concentration of NO, the mRNA and protein expression of DDAH-II as well as DDAH activity and increased the level of ADMA. Pretreatment with HDL (10, 50, or 100 μg/ml) could counteract these changes induced by ox-LDL (100 μg/ml). HDL significantly increased the attenuated endothelial cell NO production induced by ox-LDL, which was attributed to its effect on DDAH/ADMA pathway.
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Affiliation(s)
- Zhen-Yu Peng
- Department of Cardiology, Second Xiangya Hospital, Central South University, Middle Ren-Min Road 139, Changsha 410011, China
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