Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: Possible therapeutic targets?

Nitric oxide (NO) is synthetized enzymatically from l-arginine (l-Arg) by three NO synthase isoforms, iNOS, eNOS and nNOS. The synthesis of NO is selectively inhibited by guanidino-substituted analogs of l-Arg or methylarginines such as asymmetric dimethylarginine (ADMA), which results from protein...

Full description

Saved in:

Bibliographic Details
Published in:	Pharmacology & therapeutics (Oxford) Vol. 140; no. 3; pp. 239 - 257
Main Authors:	Rochette, Luc, Lorin, Julie, Zeller, Marianne, Guilland, Jean-Claude, Lorgis, Luc, Cottin, Yves, Vergely, Catherine
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier 01.12.2013
Subjects:	active sites Animals Biological and medical sciences calmodulin Cardiology and cardiovascular system Cardiovascular Diseases - drug therapy Cardiovascular Diseases - enzymology Cardiovascular Diseases - metabolism Cardiovascular system diabetes endothelial nitric oxide synthase enzyme activity enzyme inhibition Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use free radicals heme Human health and pathology Humans hypertension inducible nitric oxide synthase ischemia Life Sciences Medical sciences Miscellaneous neuronal nitric oxide synthase nitric oxide Nitric Oxide - metabolism Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - metabolism oxidation oxidative stress Oxidative Stress - drug effects Pharmacology. Drug treatments protein degradation regulatory proteins therapeutics Drug Oxidative stress Free radicals Targeting Enzyme BH Enzyme inhibitor Cardiovascular disease ADMA NO synthases Nitric-oxide synthase Free radical Research and development Treatment NO inhibitors Asymmetric dimethylarginine Oxidoreductases Mechanism of action GTP TocH alanine-glyoxylate aminotransferase 2 PRMT calmodulin AP-1 protein arginine methyl transferase glutathioneperoxidase NADPH oxidase DMGV NTPH 7,8-dihydroneopterin 30 triphosphate uric acid cationic amino acids monoamine oxidase total plasma homocysteine redox factor-1 PTPS nitric oxide AF symmetric dimethylarginine CAAs tyrosine hydroxylase cationic amino acid transporters AT ARE superoxide dismutase MAO dimethylamines ApoE-KO peroxyredoxin nuclear factor erythroid 2-related factor 2 ERK AscH(−) heat shock protein metallothionein α-keto-δ-(N(G),N(G)-dimethylguanidino)valeric acid GTP cyclohydrolase 1 mitogen-activated protein kinase S-adenosyl-l-homocysteine l-Arg Nrf2 N-nitro-l-arginine NOHA SR CATs HIF AGXT2 FMN dimethylarginine dimethylaminohydrolases SOD hypoxia-inducible factor cardiovascular CR DHFR y+LAT transporters DDAHs CV flavin mononucleotide TH PAH N(G)-monomethyl-l-arginine leukocyte telomere length forkhead protein oxidative stress extracellular signal-regulated kinase GTP-CH SDMA nuclear factor κB JNK OGG1 N-omega-hydroxy-l-arginine DM sepiapterin reductase MDA UA CaM dihydrofolate reductase NF-κB atrial fibrillation glutathione peroxidases nicotinamide dinucleotide phosphate activator protein 1 RNS Prx pterin-4a-carbinolamine dehydratase Trx malondialdehyde carbonyl reductase apolipoprotein E knockout asymmetric dimethylarginine flavin adenine dinucleotide catalases FOXO c-Jun N-terminal kinase HSP DHPR DNTP MT l-NNA FOS small interfering ribonucleic acids MAPK GPx PCD NOX CAT ROS angiotensin SAH y+L AA 6-pyruvoyl tetrahydropterin synthase SAM l-NMMA dihydropteridine reductase NADPH NO ascorbate anion tetrahydrobiopterin estimated glomerular filtration rate LTL thioredoxin glutathione diabetes mellitus tocopherol neuronal tryptophan hydroxylase Finkel–Biskis–Jinkins osteosarcoma siRNAs LDL reactive oxygen species DMA reactive nitrogen species l-arginine GSH antioxidant response element eGFR OS Ref-1 phenylalanine hydroxylase FAD GP guanosine triphosphate S-adenosyl-l-methionine low-density lipoprotein trihydrobiopterin radical 8-Oxoguanine DNA glycosylase tHcy cardiovascular disease free radicals BH 4
ISSN:	0163-7258, 1879-016X, 1879-016X, 0163-7258
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Nitric oxide (NO) is synthetized enzymatically from l-arginine (l-Arg) by three NO synthase isoforms, iNOS, eNOS and nNOS. The synthesis of NO is selectively inhibited by guanidino-substituted analogs of l-Arg or methylarginines such as asymmetric dimethylarginine (ADMA), which results from protein degradation in cells. Many disease states, including cardiovascular diseases and diabetes, are associated with increased plasma levels of ADMA. The N-terminal catalytic domain of these NOS isoforms binds the heme prosthetic group as well as the redox cofactor, tetrahydrobiopterin (BH(4)) associated with a regulatory protein, calmodulin (CaM). The enzymatic activity of NOS depends on substrate and cofactor availability. The importance of BH(4) as a critical regulator of eNOS function suggests that BH(4) may be a rational therapeutic target in vascular disease states. BH(4) oxidation appears to be a major contributor to vascular dysfunction associated with hypertension, ischemia/reperfusion injury, diabetes and other cardiovascular diseases as it leads to the increased formation of oxygen-derived radicals due to NOS uncoupling rather than NO. Accordingly, abnormalities in vascular NO production and transport result in endothelial dysfunction leading to various cardiovascular disorders. However, some disorders including a wide range of functions in the neuronal, immune and cardiovascular system were associated with the over-production of NO. Inhibition of the enzyme should be a useful approach to treat these pathologies. Therefore, it appears that both a lack and excess of NO production in diseases can have various important pathological implications. In this context, NOS modulators (exogenous and endogenous) and their therapeutic effects are discussed.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-Review-3 content type line 23
ISSN:	0163-7258 1879-016X 1879-016X 0163-7258
DOI:	10.1016/j.pharmthera.2013.07.004