Increased Arginase II Activity Contributes to Endothelial Dysfunction Through Endothelial Nitric Oxide Synthase Uncoupling in Aged Mice
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Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase
Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase Bignon, Emmanuelle; Rizza, Salvatore; Filomeni, Giuseppe; Papaleo, Elena Published in: Computational and Structural Biotechnology Journal DOI: 10.1016/j.csbj.2019.03.011 Publication date: 2019 Document version Publisher's PDF, also known as Version of record Citation for published version (APA): Bignon, E., Rizza, S., Filomeni, G., & Papaleo, E. (2019). Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase. Computational and Structural Biotechnology Journal, 17, 415- 429. https://doi.org/10.1016/j.csbj.2019.03.011 Download date: 02. Oct. 2021 Computational and Structural Biotechnology Journal 17 (2019) 415–429 Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/csbj Mini Review Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase Emmanuelle Bignon a,⁎, Salvatore Rizza b, Giuseppe Filomeni b,c, Elena Papaleo a,d,⁎⁎ a Computational Biology Laboratory, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark b Redox Signaling and Oxidative Stress Group, Cell Stress and Survival Unit, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark c Department of Biology, University of Rome Tor Vergata, Rome, Italy d Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, Denmark article info abstract Article history: Nitric oxide (NO) is an essential signaling molecule in the regulation of multiple cellular processes. It is endoge- Received 21 December 2018 nously synthesized by NO synthase (NOS) as the product of L-arginine oxidation to L-citrulline, requiring NADPH, Received in revised form 17 March 2019 molecular oxygen, and a pterin cofactor. -
Soluble Guanylate Cyclase B1-Subunit Expression Is Increased in Mononuclear Cells from Patients with Erectile Dysfunction
International Journal of Impotence Research (2006) 18, 432–437 & 2006 Nature Publishing Group All rights reserved 0955-9930/06 $30.00 www.nature.com/ijir ORIGINAL ARTICLE Soluble guanylate cyclase b1-subunit expression is increased in mononuclear cells from patients with erectile dysfunction PJ Mateos-Ca´ceres1, J Garcia-Cardoso2, L Lapuente1, JJ Zamorano-Leo´n1, D Sacrista´n1, TP de Prada1, J Calahorra2, C Macaya1, R Vela-Navarrete2 and AJ Lo´pez-Farre´1 1Cardiovascular Research Unit, Cardiovascular Institute, Hospital Clı´nico San Carlos, Madrid, Spain and 2Urology Department, Fundacio´n Jime´nez Diaz, Madrid, Spain The aim was to determine in circulating mononuclear cells from patients with erectile dysfunction (ED), the level of expression of endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC) b1-subunit and phosphodiesterase type-V (PDE-V). Peripheral mononuclear cells from nine patients with ED of vascular origin and nine patients with ED of neurological origin were obtained. Fourteen age-matched volunteers with normal erectile function were used as control. Reduction in eNOS protein was observed in the mononuclear cells from patients with ED of vascular origin but not in those from neurological origin. Although sGC b1-subunit expression was increased in mononuclear cells from patients with ED, the sGC activity was reduced. However, only the patients with ED of vascular origin showed an increased expression of PDE-V. This work shows for the first time that, independently of the aetiology of ED, the expression of sGC b1-subunit was increased in circulating mononuclear cells; however, the expression of both eNOS and PDE-V was only modified in the circulating mononuclear cells from patients with ED of vascular origin. -
Effects of Tetrahydrobiopterin on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure
J Am Soc Nephrol 11: 301–309, 2000 Effects of Tetrahydrobiopterin on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure MASAO KAKOKI,* YASUNOBU HIRATA,* HIROSHI HAYAKAWA,* ETSU SUZUKI,* DAISUKE NAGATA,* AKIHIRO TOJO,* HIROAKI NISHIMATSU,* NOBUO NAKANISHI,‡ YOSHIYUKI HATTORI,§ KAZUYA KIKUCHI,† TETSUO NAGANO,† and MASAO OMATA* *The Second Department of Internal Medicine, Faculty of Medicine, and †Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan; ‡Department of Biochemistry, Meikai University School of Dentistry, Saitama, Japan; and §Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan. Abstract. The role of nitric oxide (NO) in ischemic renal injury 4 fmol/min per g kidney; serum creatinine: control 23 Ϯ 2, is still controversial. NO release was measured in rat kidneys ischemia 150 Ϯ 27, ischemia ϩ BH4 48 Ϯ 6 M; mean Ϯ subjected to ischemia and reperfusion to determine whether SEM). Most of renal NOS activity was calcium-dependent, and (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), a cofactor of NO its activity decreased in the ischemic kidney. However, it was synthase (NOS), reduces ischemic injury. Twenty-four hours restored by BH4 (control 5.0 Ϯ 0.9, ischemia 2.2 Ϯ 0.4, after bilateral renal arterial clamp for 45 min, acetylcholine- ischemia ϩ BH4 4.3 Ϯ 1.2 pmol/min per mg protein). Immu- induced vasorelaxation and NO release were reduced and renal noblot after low-temperature sodium dodecyl sulfate-polyac- excretory function was impaired in Wistar rats. Administration rylamide gel electrophoresis revealed that the dimeric form of of BH4 (20 mg/kg, by mouth) before clamping resulted in a endothelial NOS decreased in the ischemic kidney and that it marked improvement of those parameters (10Ϫ8 M acetylcho- was restored by BH4. -
Synthase from Rat Liver
Proc. Nati. Acad. Sci. USA Vol. 89, pp. 5361-5365, June 1992 Biochemistry Purification of a distinctive form of endotoxin-induced nitric oxide synthase from rat liver (endothelium-derived relaxing factor/L-arginine/calmodulin) TOM EVANS, ADAM CARPENTER, AND JONATHAN COHEN* Department of Infectious Diseases, Royal Postgraduate Medical School, Du Cane Road, London W12 ONN, United Kingdom Communicated by Robert F. Furchgott, March 6, 1992 (received for review November 18, 1991) ABSTRACT An endotoxin-induced form of nitric oxide We are interested in the hepatic form of the NO synthase, synthase (EC 1.14.23) was purified to homogeneity from rat which is induced by the administration of endotoxin (8). liver by sequential anion-exchange chromatography and afflin- Livers from untreated animals show minimal NO synthase ity chromatography using 2',5'-ADP-Sepharose. The enzyme activity. NO production in the liver seems to suppress protein has a subunit molecular mass of 135 kDa as determined by synthesis and protects the liver against damage (18). We have SDS/PAGE, a maximum specific activity of 462 nmol of purified this enzyme to homogeneity and show that it is citrulline formed from arginine per min per mg, and a K. for strongly stimulated by calmodulin, whereas its activity is arginine of 11 jIM. The enzyme was strongly stimulated by the only affected to a small degree by free calcium concentra- addition of calmodulin with an EC50 of 2 nM, but removal of tions-even in the presence ofcalmodulin. Thus, this hepatic free calcium from the assay medium only reduced activity by endotoxin-induced NO synthase is distinct from that de- 15%. -
Effect of Arginase Inhibition on Ischemia-Reperfusion Injury in Patients with Coronary Artery Disease with and Without Diabetes Mellitus
Effect of Arginase Inhibition on Ischemia-Reperfusion Injury in Patients with Coronary Artery Disease with and without Diabetes Mellitus Oskar Ko¨ vamees*, Alexey Shemyakin, John Pernow Department of Medicine, Karolinska Institutet, Stockholm, Sweden Abstract Background: Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes (Clinical trial registration number: NCT02009527). Methods: Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nv-hydroxy-nor- L-arginine, 0.1 mg/min) or saline. Results: The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.765.2% to 7.964.0% during saline administration (P,0.05). Nv-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.364.3% at baseline vs. 11.563.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P,0.01). -
Nitric Oxide Synthase Inhibitors As Antidepressants
Pharmaceuticals 2010, 3, 273-299; doi:10.3390/ph3010273 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review Nitric Oxide Synthase Inhibitors as Antidepressants Gregers Wegener 1,* and Vallo Volke 2 1 Centre for Psychiatric Research, University of Aarhus, Skovagervej 2, DK-8240 Risskov, Denmark 2 Department of Physiology, University of Tartu, Ravila 19, EE-70111 Tartu, Estonia; E-Mail: [email protected] (V.V.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +4577893524; Fax: +4577893549. Received: 10 November 2009; in revised form: 7 January 2010 / Accepted: 19 January 2010 / Published: 20 January 2010 Abstract: Affective and anxiety disorders are widely distributed disorders with severe social and economic effects. Evidence is emphatic that effective treatment helps to restore function and quality of life. Due to the action of most modern antidepressant drugs, serotonergic mechanisms have traditionally been suggested to play major roles in the pathophysiology of mood and stress-related disorders. However, a few clinical and several pre-clinical studies, strongly suggest involvement of the nitric oxide (NO) signaling pathway in these disorders. Moreover, several of the conventional neurotransmitters, including serotonin, glutamate and GABA, are intimately regulated by NO, and distinct classes of antidepressants have been found to modulate the hippocampal NO level in vivo. The NO system is therefore a potential target for antidepressant and anxiolytic drug action in acute therapy as well as in prophylaxis. This paper reviews the effect of drugs modulating NO synthesis in anxiety and depression. Keywords: nitric oxide; antidepressants; psychiatry; depression; anxiety 1. Introduction Recent data from Denmark and Europe [1,2], indicate that brain disorders account for 12% of all direct costs in the Danish health system and 9% of the total drug consumption was used for treatment of brain diseases. -
Nitric Oxide Synthase Inhibitors
Chapter 12 Nitric Oxide Synthase Inhibitors Elizabeth Igne Ferreira and Ricardo Augusto Massarico Serafim Additional information is available at the end of the chapter http://dx.doi.org/10.5772/67027 Abstract Nitric oxide (NO) is an endogenic product from plants, bacteria, and animal cells that has many important effects in those organisms. It is produced by nitric oxide synthase (NOS), which is found in main three isoforms, namely endothelial NOS (eNOS), induc- ible NOS (iNOS), and neuronal NOS (nNOS). It has an important role in homeostasis in different physiological systems, such as micro- and macro-vascularization, inhibition of platelet aggregation, and neurotransmission regulation in the central nervous, gastroin- testinal, respiratory, and genitourinary systems. However, its overproduction has been associated with diseases such as arthritis, asthma, cerebral ischemia, Parkinson’s disease, neurodegeneration, and seizures. For this reason, and due to better understanding of the molecular mechanisms by which NO provokes those diseases, the interest on the design of NOS inhibitors with therapeutic purposes has highly increased. Based on the forego - ing considerations, the proposal of this chapter is to show an overview about the design strategies, mechanism of action at the molecular level, and the main advances toward the search for selective NOS inhibitors available in the literature. Keywords: nitric oxide synthase isoforms, structure-based drug design, enzymatic inhibition, selectivity, heterocyclic compounds 1. Introduction Nitric oxide (NO) is a diatomic neutral molecule, produced by bacteria, plants, and animals. Having one unpaired electron, its effect in biological system is related to the stabilization of this electron. It acts as dissolved nonelectrolyte in the organisms, except for the lungs, where it is found in gaseous state [1–3]. -
Effects of Γ-Aminobutyric Acid on the Erectogenic Properties of Sildenafil
Available online on www.ijtpr.com International Journal of Toxicological and Pharmacological Research 2017; 9(3); 234-243 ISSN: 0975-5160 Research Article Effects of γ-Aminobutyric Acid on the Erectogenic Properties of Sildenafil Adefegha S A1*, Oyeleye S I1,2 Oboh G1 1Functional food and Nutraceutical Laboratory, Department of Biochemistry, Federal University of Technology, Akure, P.M.B. 704, Akure 340001, Nigeria 2Department of Biomedical Technology, Federal University of Technology, Akure, P.M.B. 704, Akure 340001, Nigeria Available Online:25th July, 2017 ABSTRACT Erectile dysfunction (ED) is a disorder of increasing socio-economic burden. Therapeutic drugs such as sildenafil have been in use for the treatment of ED, but with their associated side effects. γ-aminobutyric acid (GABA) is a neurotransmitter with possible vasodilatory properties. In this study, the effect of GABA on the erectogenic properties of sildenafil was investigated. Aqueous solution of GABA and sildenafil (1 mM) was separately prepared as well as the mixtures of both (75% GABA + 25% sildenafil; 50% GABA + 50% sildenafil; 25% GABA + 75% sildenafil). Thereafter, the in vitro effects of all the studied samples on the activities of arginase, angiotensin-I converting enzyme (ACE) and acetylcholinesterase (AChE) were investigated. The results revealed that all the samples inhibited arginase, ACE and AChE activities. Considering the various combinations, 25% GABA + 75% sildenafil had the highest arginase inhibitory effect, 50% GABA + 50% sildenafil showed the highest ACE inhibiting effect, while 25% GABA + 75% sildenafil exhibited the highest AChE inhibitory effect. Therefore, the observed enzyme inhibiting effect of sildenafil, GABA and their various combinations on rat penile arginase, ACE and AChE activities could be part of the mechanism by which they elicit their erectogenic properties. -
Modulation of Retinal Dopaminergic Cells by Nitric Oxide. a Protective Effect on NMDA-Induced Retinal Injury
in vivo 18: 311-316 (2004) Review Modulation of Retinal Dopaminergic Cells by Nitric Oxide. A Protective Effect on NMDA-induced Retinal Injury YASUSHI KITAOKA1 and TOSHIO KUMAI2 Departments of 1Ophthalmology and 2Pharmacology, St Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan Abstract. Nitric oxide (NO) may play an important role in experimental glaucoma (7). Thus, the involvement of regulating retinal neuronal survival. While the precise impact of elevated vitreal glutamate in glaucoma is not well NO mechanisms on retinal neurons remains to be elucidated, it established. Nonetheless, an understanding of the has been reported that low doses of NO may have a biochemical mechanism by which glutamate regulates neuroprotective effect against N-methyl-D-aspartate (NMDA)- retinal neuronal survival is important in developing induced retinal neurotoxicity. Dopamine has also been therapeutics for protecting retinal neuronal cells at the recognized to have neuroprotective actions. Retinal dopaminergic injured site in several ocular disorders including glaucoma, cells can be detected by the immunohistochemical staining of ischemia (8,9) and optic neuropathy (10,11). tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. We observed that NMDA dramatically decreased in TH NMDA-induced neurotoxicity immunostaining at the junction between the inner nuclear layer and inner plexiform layer, and that this reduction in The excitotoxic effect of glutamate on the retinal neuronal immunostaining was attenuated by the co-injection of NOC 18, cells has been well demonstrated. Among the several an NO donor. Thus, the current review focused on the NO- glutamate receptors, activation of the N-methyl-D-aspartate dopamine interactions in the retinal neuroprotection. -
Competitive Metabolism of L-Arginine: Arginase As a Therapeutic Target In
JBR Journal of Biomedical Research,2011,25(5):299-308 http://elsevier.com/wps/ Review find/journaldescription.cws_ home/723905/description#description Competitive metabolism of L-arginine: arginase as a therapeutic ☆ target in asthma * Jennifer M. Bratt, Amir A. Zeki, Jerold A. Last, Nicholas J. Kenyon Department of Internal Medicine, Division of Pulmonary and Critical Care and Sleep Medicine, University of California, Davis, CA 95616, USA Received 25 April 2011, Revised 24 June 2011, Accepted 21 July 2011 Abstract Exhaled breath nitric oxide (NO) is an accepted asthma biomarker. Lung concentrations of NO and its amino acid precursor, L-arginine, are regulated by the relative expressions of the NO synthase (NOS) and arginase iso- forms. Increased expression of arginase I and NOS2 occurs in murine models of allergic asthma and in biopsies of asthmatic airways. Although clinical trials involving the inhibition of NO-producing enzymes have shown mixed results, small molecule arginase inhibitors have shown potential as a therapeutic intervention in animal and cell culture models. Their transition to clinical trials is hampered by concerns regarding their safety and potential tox- icity. In this review, we discuss the paradigm of arginase and NOS competition for their substrate L-arginine in the asthmatic airway. We address the functional role of L-arginine in inflammation and the potential role of arginase inhibitors as therapeutics. Keywords: nitric oxide, L-arginine, arginase, nor-NOHA, nitrosation, nitric oxide synthase INTRODUCTION from accumulation of collagens in the submucosal and [3] Asthma is a common disease characterized by a reticular basement membrane . The airway remod- syndrome of persistent airway inflammation and re- eling and resultant reduction in overall lung function versible airway obstruction. -
Increased Arginine Amino Aciduria/Urea Cycle Disorder
Newborn Screening ACT Sheet Increased Arginine Amino Aciduria/Urea Cycle Disorder Differential Diagnosis: Argininemia (ARG) Condition Description: The urea cycle is the enzyme cycle whereby ammonia is converted to urea. In argininemia, defects in arginase, a urea cycle enzyme, may result in hyperammonemia. Take the Following IMMEDIATE Actions • Contact family to inform them of the newborn screening result and ascertain clinical status (poor feeding, vomiting, lethargy, tachypnea). • Immediate telephone consultation with pediatric metabolic specialist. (See attached list.) • Evaluate the newborn (poor feeding, vomiting, lethargy, hypotonia, tachypnea, seizures and signs of liver disease). • If any sign is present or infant is ill, IMMEDIATELY initiate emergency treatment for hyperammonemia in consultation with metabolic specialist. • Transport to hospital for further treatment in consultation with metabolic specialist. • Initiate timely confirmatory/diagnostic testing and management, as recommended by specialist. • Initial testing: immediate plasma ammonia, plasma quantitative amino acids, and urine orotic acid. • Repeat newborn screen if second screen has not been done. • Provide family with basic information about hyperammonemia. • Report findings to newborn screening program. Diagnostic Evaluation: Specific diagnosis is made by plasma quantitative amino acid analysis revealing increased arginine and urine orotic acid analysis revealing increased orotic acid, respectively. Blood ammonia determination may also reveal hyperammonemia. Clinical -
Arginase Deficiency
Arginase Deficiency Lauren Ballard, Alex Belardo, Lainie Boyle, Abby Dryden, Rachel Kirchner, M’Lynn Gwinner, Shreya Nalluri, & Julia Slogar Service Learning Initiative in Biochemistry 5614 (Autumn 2018) Argininemia: An autosomal recessive disorder Video on Inheritance Patterns HNEkidshealth. “Autosomal Recessive Inheritance - Genetics.” YouTube, YouTube, 30 Mar. 2015, www.youtube.com/watch?v=Nv6qUsKYodA. Argininemia ● Inherited disorder that causes arginine (amino acid) and ammonia to build up in the blood ● The deficiency usually becomes evident by 3 years of age ● Occurs once in every 300,000 to 1,000,000 individuals ● Caused by a mutation in the ARG1 gene, which encodes the enzyme arginase Baby's first foods: Where to begin? Digital image retrieved ● Inherited in an autosomal recessive pattern October 31, 2018 from https://www.kabritausa.com/blog/babys-first-foods-begin/ Protein Metabolism Amino acids Peptide Protein How Your Body Uses Amino Acids as Proteins. Digital image retrieved October 31, 2018 https://socratic.org/questions/amino-acids-as-monomers-of-protein ● Amino Acids are the building blocks of proteins ● Dietary protein must be broken down into amino acids Protein Metabolism + NH4 Urea (waste) Dietary Protein Amino Acids Carbon Glucose backbone (energy) Intracellular Protein Argininemia and the Urea Cycle ● Disorder of the urea cycle ● Our bodies produce ammonia as metabolic waste - Ammonia is highly toxic and must be discarded ● The urea cycle in the liver converts ammonia to urea, a less toxic compound Urea Cycle. Digital image retrieved October 31, 2018 from https://www.slideshare.net/YESANNA/urea-cycle-44200147 What is Argininemia? ● Disorder of the urea cycle ● Dysfunctional arginase enzyme disrupts final step of urea cycle ● Build-up of ammonia in the blood X Urea Cycle.