{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:41:56Z","timestamp":1792104116368,"version":"4.4.0"},"reference-count":187,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T00:00:00Z","timestamp":1697328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"the British Heart Foundation Centre of Research Excellence, King\u2019s College London","doi-asserted-by":"publisher","award":["RE19542"],"award-info":[{"award-number":["RE19542"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics.<\/jats:p>","DOI":"10.3390\/ijms242015200","type":"journal-article","created":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T10:47:32Z","timestamp":1697366852000},"page":"15200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential"],"prefix":"10.3390","volume":"24","author":[{"given":"Roman","family":"Roy","sequence":"first","affiliation":[{"name":"Cardiovascular Department, King\u2019s College Hospital NHS Foundation Trust, London SE5 9RS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Wilcox","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Webb","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, British Heart Foundation Centre, School of Cardiovascular and Metabolic Medicine and Sciences, King\u2019s College London, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"O\u2019Gallagher","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, King\u2019s College Hospital NHS Foundation Trust, London SE5 9RS, UK"},{"name":"British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King\u2019s College London, London SE5 9NU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/416337a","article-title":"Nitric Oxide Regulates the Heart by Spatial Confinement of Nitric Oxide Synthase Isoforms","volume":"416","author":"Barouch","year":"2002","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.1016\/j.cell.2022.06.010","article-title":"Nitric Oxide Signaling in Health and Disease","volume":"185","author":"Lundberg","year":"2022","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/cvr\/cvab155","article-title":"Neuronal Nitric Oxide Synthase Regulates Regional Brain Perfusion in Healthy Humans","volume":"118","author":"Puledda","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/med.21599","article-title":"Inducible Nitric Oxide Synthase: Regulation, Structure, and Inhibition","volume":"40","author":"Cinelli","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ahmad, A., Dempsey, S., Daneva, Z., Azam, M., Li, N., Li, P.-L., and Ritter, J. (2018). Role of Nitric Oxide in the Cardiovascular and Renal Systems. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092605"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1152\/jappl.2001.91.3.1421","article-title":"Invited Review: CGMP-Dependent Protein Kinase Signaling Mechanisms in Smooth Muscle: From the Regulation of Tone to Gene Expression","volume":"91","author":"Lincoln","year":"2001","journal-title":"J. Appl. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fernando, V., Zheng, X., Walia, Y., Sharma, V., Letson, J., and Furuta, S. (2019). S-Nitrosylation: An Emerging Paradigm of Redox Signaling. Antioxidants, 8.","DOI":"10.3390\/antiox8090404"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.freeradbiomed.2021.07.002","article-title":"Protein S-Nitrosylation and Oxidation Contribute to Protein Misfolding in Neurodegeneration","volume":"172","author":"Nakamura","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.1007\/s11064-020-03136-6","article-title":"The Relationship Between Protein S-Nitrosylation and Human Diseases: A Review","volume":"45","author":"Zhang","year":"2020","journal-title":"Neurochem. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gantner, B.N., LaFond, K.M., and Bonini, M.G. (2020). Nitric Oxide in Cellular Adaptation and Disease. Redox Biol., 34.","DOI":"10.1016\/j.redox.2020.101550"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1161\/01.HYP.23.6.1121","article-title":"Nitric Oxide Synthase Isozymes. Characterization, Purification, Molecular Cloning, and Functions","volume":"23","author":"Closs","year":"1994","journal-title":"Hypertension"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.niox.2019.04.011","article-title":"Targeting Nitric Oxide as a Key Modulator of Sepsis, Arthritis and Pain","volume":"89","author":"Spiller","year":"2019","journal-title":"Nitric Oxide"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"32515","DOI":"10.1074\/jbc.271.51.32515","article-title":"Nitric Oxide Binding to the Heme of Neuronal Nitric-Oxide Synthase Links Its Activity to Changes in Oxygen Tension","volume":"271","author":"Rousseau","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1172\/JCI1378","article-title":"Nitric Oxide Synthesis in the Lung. Regulation by Oxygen through a Kinetic Mechanism","volume":"101","author":"Dweik","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9254","DOI":"10.1073\/pnas.0700332104","article-title":"A Connecting Hinge Represses the Activity of Endothelial Nitric Oxide Synthase","volume":"104","author":"Haque","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"C803","DOI":"10.1152\/ajpcell.00457.2005","article-title":"Transcriptional and Posttranscriptional Regulation of Endothelial Nitric Oxide Synthase Expression","volume":"291","author":"Searles","year":"2006","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nrcardio.2017.224","article-title":"Nitric Oxide Signalling in Cardiovascular Health and Disease","volume":"15","author":"Farah","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1161\/CIRCULATIONAHA.108.822205","article-title":"Effects of Neuronal Nitric Oxide Synthase on Human Coronary Artery Diameter and Blood Flow In Vivo","volume":"119","author":"Seddon","year":"2009","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1161\/CIRCULATIONAHA.107.744540","article-title":"Neuronal Nitric Oxide Synthase Regulates Basal Microvascular Tone in Humans In Vivo","volume":"117","author":"Seddon","year":"2008","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"H106","DOI":"10.1152\/ajpheart.00561.2018","article-title":"Elevated Arterial Shear Rate Increases Indexes of Endothelial Cell Autophagy and Nitric Oxide Synthase Activation in Humans","volume":"316","author":"Park","year":"2019","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ccc.2019.12.009","article-title":"Nitric Oxide and Endothelial Dysfunction","volume":"36","author":"Cyr","year":"2020","journal-title":"Crit. Care Clin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/14017431.2019.1581943","article-title":"Effect of Nitric Oxide Reduction on Arterial Thrombosis","volume":"53","author":"Costa","year":"2019","journal-title":"Scand. Cardiovasc. J."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Theofilis, P., Sagris, M., Oikonomou, E., Antonopoulos, A.S., Siasos, G., Tsioufis, C., and Tousoulis, D. (2021). Inflammatory Mechanisms Contributing to Endothelial Dysfunction. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070781"},{"key":"ref_24","first-page":"153","article-title":"Endothelial Nitric Oxide Synthase (ENOS) and the Cardiovascular System: In Physiology and in Disease States","volume":"15","author":"Tran","year":"2022","journal-title":"Am. J. Biomed. Sci. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1152\/physrev.00036.2017","article-title":"Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation","volume":"99","author":"Tejero","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1161\/CIRCRESAHA.107.158410","article-title":"Platelet-Derived Nitric Oxide Signaling and Regulation","volume":"101","author":"Gkaliagkousi","year":"2007","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.bcp.2019.05.030","article-title":"Nitric Oxide-Enhancing or -Releasing Agents as Antithrombotic Drugs","volume":"166","author":"Gresele","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3782","DOI":"10.1073\/pnas.0408310102","article-title":"Regulation of Platelet Granule Exocytosis by S-Nitrosylation","volume":"102","author":"Morrell","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1161\/ATVBAHA.119.312836","article-title":"Endothelial Dysfunction","volume":"39","author":"Corban","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"798958","DOI":"10.3389\/fmed.2021.798958","article-title":"Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications","volume":"8","author":"Gallo","year":"2022","journal-title":"Front. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s10741-019-09881-3","article-title":"Role of Endothelial Dysfunction in Heart Failure","volume":"25","author":"Zuchi","year":"2020","journal-title":"Heart Fail. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1161\/hc2901.091399","article-title":"Accelerated Atherosclerosis, Aortic Aneurysm Formation, and Ischemic Heart Disease in Apolipoprotein E\/Endothelial Nitric Oxide Synthase Double-Knockout Mice","volume":"104","author":"Kuhlencordt","year":"2001","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00011-019-01229-9","article-title":"Roles of ENOS in Atherosclerosis Treatment","volume":"68","author":"Hong","year":"2019","journal-title":"Inflamm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Man, A.W.C., Zhou, Y., Xia, N., and Li, H. (2022). Endothelial Nitric Oxide Synthase in the Perivascular Adipose Tissue. Biomedicines, 10.","DOI":"10.3390\/biomedicines10071754"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1152\/physrev.00042.2007","article-title":"ENOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues","volume":"89","author":"Balligand","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1161\/01.RES.0000088351.58510.21","article-title":"Nitric Oxide and Cardiac Function","volume":"93","author":"Massion","year":"2003","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.cardiores.2007.04.031","article-title":"Cardiomyocytes as Effectors of Nitric Oxide Signalling","volume":"75","author":"Seddon","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s11010-009-0219-x","article-title":"Nitric Oxide and Nitric Oxide Synthase Isoforms in the Normal, Hypertrophic, and Failing Heart","volume":"333","author":"Umar","year":"2010","journal-title":"Mol. Cell Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"H429","DOI":"10.1152\/ajpheart.00501.2001","article-title":"Neuronal NOS-Dependent Dilation to Flow in Coronary Arteries of Male ENOS-KO Mice","volume":"282","author":"Huang","year":"2002","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1096\/fj.01-0842com","article-title":"Vascular Smooth Muscle and Nitric Oxide Synthase","volume":"16","author":"Buchwalow","year":"2002","journal-title":"FASEB J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00424-003-1232-7","article-title":"An in Vitro Investigation of Aorta and Corpus Cavernosum from ENOS and NNOS Gene-Deficient Mice","volume":"448","author":"Cotter","year":"2004","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000317395","article-title":"Modulation of Renal Blood Flow and Vascular Tone by Neuronal Nitric Oxide Synthase-Derived Nitric Oxide","volume":"48","author":"Toda","year":"2011","journal-title":"J. Vasc. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.tcm.2010.02.007","article-title":"Neuronal Nitric Oxide Synthase and Human Vascular Regulation","volume":"19","author":"Melikian","year":"2009","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1161\/HYPERTENSIONAHA.116.08792","article-title":"Blood Pressure in Healthy Humans Is Regulated by Neuronal NO Synthase","volume":"69","author":"Shabeeh","year":"2017","journal-title":"Hypertension"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.niox.2020.06.004","article-title":"Role of Neuronal Nitric Oxide Synthase on Cardiovascular Functions in Physiological and Pathophysiological States","volume":"102","author":"Ally","year":"2020","journal-title":"Nitric Oxide"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.pharmthera.2004.11.003","article-title":"Cardiac Nitric Oxide: Emerging Role for NNOS in Regulating Physiological Function","volume":"106","author":"Danson","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1113\/jphysiol.2013.270306","article-title":"Molecular Mechanisms of Neuronal Nitric Oxide Synthase in Cardiac Function and Pathophysiology","volume":"592","author":"Zhang","year":"2014","journal-title":"J. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1136\/hrt.2005.068270","article-title":"Oxidative Stress and Redox Signalling in Cardiac Hypertrophy and Heart Failure","volume":"93","author":"Seddon","year":"2007","journal-title":"Heart"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1161\/CIRCRESAHA.122.321631","article-title":"The Effect of a Neuronal Nitric Oxide Synthase Inhibitor on Neurovascular Regulation in Humans","volume":"131","author":"Rosentreter","year":"2022","journal-title":"Circ. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1152\/physrev.00022.2020","article-title":"Regulation of Cerebral Blood Flow in Humans: Physiology and Clinical Implications of Autoregulation","volume":"101","author":"Claassen","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1177\/0271678X15617954","article-title":"Neurovascular Coupling in Humans: Physiology, Methodological Advances and Clinical Implications","volume":"36","author":"Phillips","year":"2016","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"H559","DOI":"10.1152\/ajpheart.1997.272.1.H559","article-title":"Neuronal NOS-Derived NO Plays Permissive Role in Cerebral Blood Flow Response to Hypercapnia","volume":"272","author":"Okamoto","year":"1997","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"H982","DOI":"10.1152\/ajpheart.1998.274.3.H982","article-title":"Nitric Oxide from Neuronal NOS Plays Critical Role in Cerebral Capillary Flow Response to Hypoxia","volume":"274","author":"Hudetz","year":"1998","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1515\/revneuro-2019-0111","article-title":"Neurophysiologic Implications of Neuronal Nitric Oxide Synthase","volume":"31","author":"Hosseini","year":"2020","journal-title":"Rev. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"H578","DOI":"10.1152\/ajpheart.00745.2016","article-title":"The Human Coronary Vasodilatory Response to Acute Mental Stress Is Mediated by Neuronal Nitric Oxide Synthase","volume":"313","author":"Khan","year":"2017","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1161\/HYPERTENSIONAHA.114.04538","article-title":"Impaired Neuronal Nitric Oxide Synthase\u2013Mediated Vasodilator Responses to Mental Stress in Essential Hypertension","volume":"65","author":"Khan","year":"2015","journal-title":"Hypertension"},{"key":"ref_57","unstructured":"Hemmens, B., and Mayer, B. (1998). Nitric Oxide Protocols, Humana Press."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"22789","DOI":"10.1016\/S0021-9258(18)54421-5","article-title":"Purification of the Inducible Murine Macrophage Nitric Oxide Synthase. Identification as a Flavoprotein","volume":"266","author":"Hevel","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6435","DOI":"10.1074\/jbc.271.11.6435","article-title":"Identification, Characterization, and Comparison of the Calmodulin-Binding Domains of the Endothelial and Inducible Nitric Oxide Synthases","volume":"271","author":"Venema","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"536","DOI":"10.12688\/f1000research.51270.2","article-title":"Nitric Oxide for the Prevention and Treatment of Viral, Bacterial, Protozoal and Fungal Infections","volume":"10","author":"Bath","year":"2021","journal-title":"F1000Res"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/S1286-4579(03)00096-0","article-title":"Inducible Nitric Oxide Synthase and Control of Intracellular Bacterial Pathogens","volume":"5","author":"Chakravortty","year":"2003","journal-title":"Microbes Infect."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12974-019-1516-2","article-title":"Neuroinflammation: Friend and Foe for Ischemic Stroke","volume":"16","author":"Jayaraj","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s12079-021-00663-x","article-title":"The Modulation of Neuroinflammation by Inducible Nitric Oxide Synthase","volume":"16","author":"Justo","year":"2022","journal-title":"J. Cell Commun. Signal"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Kr\u00f3l, M., and Kepinska, M. (2020). Human Nitric Oxide Synthase\u2014Its Functions, Polymorphisms, and Inhibitors in the Context of Inflammation, Diabetes and Cardiovascular Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010056"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.biopha.2017.06.036","article-title":"Inducible Nitric Oxide Synthase: Good or Bad?","volume":"93","author":"Lind","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.biopha.2017.10.122","article-title":"Nitric Oxide Bioavailability Dysfunction Involves in Atherosclerosis","volume":"97","author":"Chen","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1097\/01.CCM.0000105581.01815.C6","article-title":"Multiple-Center, Randomized, Placebo-Controlled, Double-Blind Study of the Nitric Oxide Synthase Inhibitor 546C88: Effect on Survival in Patients with Septic Shock*","volume":"32","author":"Lorente","year":"2004","journal-title":"Crit. Care Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"eabj5070","DOI":"10.1126\/scitranslmed.abj5070","article-title":"A Phase 1\/2 Clinical Trial of the Nitric Oxide Synthase Inhibitor L-NMMA and Taxane for Treating Chemoresistant Triple-Negative Breast Cancer","volume":"13","author":"Chung","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/10623320490482619","article-title":"Peroxynitrite and Vascular Endothelial Dysfunction in Diabetes Mellitus","volume":"11","author":"Zou","year":"2004","journal-title":"Endothelium"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"H1829","DOI":"10.1152\/ajpheart.00230.2009","article-title":"ENOS Uncoupling and Endothelial Dysfunction in Aged Vessels","volume":"297","author":"Yang","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.niox.2019.04.007","article-title":"Site and Mechanism of Uncoupling of Nitric-Oxide Synthase: Uncoupling by Monomerization and Other Misconceptions","volume":"89","author":"Gebhart","year":"2019","journal-title":"Nitric Oxide"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1161\/CIRCRESAHA.121.318063","article-title":"Oxidative Stress and Hypertension","volume":"128","author":"Griendling","year":"2021","journal-title":"Circ. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1089\/ars.2020.8112","article-title":"Oxidative Stress, GTPCH1, and Endothelial Nitric Oxide Synthase Uncoupling in Hypertension","volume":"34","author":"Wu","year":"2021","journal-title":"Antioxid. Redox Signal"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s40885-016-0055-8","article-title":"Neuronal Nitric Oxide Synthase in Hypertension\u2014An Update","volume":"22","author":"Zhang","year":"2016","journal-title":"Clin. Hypertens."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Gliozzi, M., Scicchitano, M., Bosco, F., Musolino, V., Carresi, C., Scarano, F., Maiuolo, J., Nucera, S., Maretta, A., and Paone, S. (2019). Modulation of Nitric Oxide Synthases by Oxidized LDLs: Role in Vascular Inflammation and Atherosclerosis Development. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133294"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"117443","DOI":"10.1016\/j.lfs.2020.117443","article-title":"The Mechanisms of Lysophosphatidylcholine in the Development of Diseases","volume":"247","author":"Liu","year":"2020","journal-title":"Life Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1111\/bph.14167","article-title":"Eicosanoids, Prostacyclin and Cyclooxygenase in the Cardiovascular System","volume":"176","author":"Mitchell","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_78","unstructured":"Pong, T., and Huang, P.L. (2015). Atherosclerosis, John Wiley & Sons, Inc."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1161\/01.ATV.0000223143.88128.19","article-title":"Atheroprotective Effects of Neuronal Nitric Oxide Synthase in Apolipoprotein E Knockout Mice","volume":"26","author":"Kuhlencordt","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"206","DOI":"10.3389\/fphys.2016.00206","article-title":"Neuronal Nitric Oxide Synthase in Vascular Physiology and Diseases","volume":"7","author":"Costa","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.ijcard.2019.11.004","article-title":"Improvement in Endothelial Function in Cardiovascular Disease\u2014Is Arginase the Target?","volume":"301","author":"Mahdi","year":"2020","journal-title":"Int. J. Cardiol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Janaszak-Jasiecka, A., P\u0142oska, A., Wiero\u0144ska, J.M., Dobrucki, L.W., and Kalinowski, L. (2023). Endothelial Dysfunction Due to ENOS Uncoupling: Molecular Mechanisms as Potential Therapeutic Targets. Cell Mol. Biol. Lett., 28.","DOI":"10.1186\/s11658-023-00423-2"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1007\/s00424-016-1839-0","article-title":"The ENOS Signalosome and Its Link to Endothelial Dysfunction","volume":"468","author":"Siragusa","year":"2016","journal-title":"Pflug. Arch."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1161\/hc3601.094298","article-title":"Endothelial Nitric Oxide Synthase Limits Left Ventricular Remodeling After Myocardial Infarction in Mice","volume":"104","author":"Ullrich","year":"2001","journal-title":"Circulation"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1161\/CIRCULATIONAHA.105.557892","article-title":"Deficiency of Neuronal Nitric Oxide Synthase Increases Mortality and Cardiac Remodeling After Myocardial Infarction","volume":"112","author":"Saraiva","year":"2005","journal-title":"Circulation"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1161\/CIRCULATIONAHA.105.539437","article-title":"NNOS Gene Deletion Exacerbates Pathological Left Ventricular Remodeling and Functional Deterioration After Myocardial Infarction","volume":"112","author":"Dawson","year":"2005","journal-title":"Circulation"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/S0008-6363(01)00394-7","article-title":"The Contribution of Endothelial Nitric Oxide Synthase to Early Ischaemic Preconditioning: The Lowering of the Preconditioning Threshold. An Investigation in ENOS Knockout Mice","volume":"52","author":"Bell","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1161\/01.CIR.98.5.441","article-title":"Nitric Oxide Synthase Is the Mediator of Late Preconditioning against Myocardial Infarction in Conscious Rabbits","volume":"98","author":"Takano","year":"1998","journal-title":"Circulation"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1006\/jmcc.2001.1462","article-title":"Cardioprotective Function of Inducible Nitric Oxide Synthase and Role of Nitric Oxide in Myocardial Ischemia and Preconditioning: An Overview of a Decade of Research","volume":"33","author":"Bolli","year":"2001","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Lee, H.-M., Choi, J.W., and Choi, M.S. (2021). Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury. Antioxidants, 11.","DOI":"10.3390\/antiox11010057"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"107819","DOI":"10.1016\/j.pharmthera.2021.107819","article-title":"Nitrite and Myocardial Ischaemia Reperfusion Injury. Where Are We Now?","volume":"223","author":"Griffiths","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"H1567","DOI":"10.1152\/ajpheart.1999.276.5.H1567","article-title":"Myocardial Ischemia-Reperfusion Injury Is Exacerbated in Absence of Endothelial Cell Nitric Oxide Synthase","volume":"276","author":"Jones","year":"1999","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"H276","DOI":"10.1152\/ajpheart.00129.2003","article-title":"Endothelial Nitric Oxide Synthase Overexpression Attenuates Myocardial Reperfusion Injury","volume":"286","author":"Jones","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41586-019-1100-z","article-title":"Nitrosative Stress Drives Heart Failure with Preserved Ejection Fraction","volume":"568","author":"Schiattarella","year":"2019","journal-title":"Nature"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"H219","DOI":"10.1152\/ajpheart.2002.282.1.H219","article-title":"Decreased Expression of Myocardial ENOS and Caveolin in Dogs with Hypertrophic Cardiomyopathy","volume":"282","author":"Piech","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/S0735-1097(98)00336-2","article-title":"Expression, Activity and Functional Significance of Inducible Nitric Oxide Synthase in the Failing Human Heart","volume":"32","author":"Drexler","year":"1998","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/S0140-6736(04)16048-0","article-title":"Increased Neuronal Nitric Oxide Synthase-Derived NO Production in the Failing Human Heart","volume":"363","author":"Damy","year":"2004","journal-title":"Lancet"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"H2144","DOI":"10.1152\/ajpheart.00591.2005","article-title":"Increased Expression of INOS Is Associated with Endothelial Dysfunction and Impaired Pressor Responsiveness in Streptozotocin-Induced Diabetes","volume":"289","author":"Nagareddy","year":"2005","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s00395-009-0077-4","article-title":"Cardioselective Nitric Oxide Synthase 3 Gene Transfer Protects against Myocardial Reperfusion Injury","volume":"105","author":"Szelid","year":"2010","journal-title":"Basic. Res. Cardiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1161\/01.RES.0000126497.38281.23","article-title":"Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction","volume":"94","author":"Janssens","year":"2004","journal-title":"Circ. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"4891","DOI":"10.1073\/pnas.0837428100","article-title":"Endothelial Nitric Oxide Synthase Overexpression Attenuates Congestive Heart Failure in Mice","volume":"100","author":"Jones","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1016\/j.lfs.2004.11.028","article-title":"Human Endothelial Nitric Oxide Synthase Gene Delivery Protects against Cardiac Remodeling and Reduces Oxidative Stress after Myocardial Infarction","volume":"76","author":"Smith","year":"2005","journal-title":"Life Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.niox.2014.08.004","article-title":"Nitric Oxide Synthases and Diabetic Cardiomyopathy","volume":"43","author":"Khanna","year":"2014","journal-title":"Nitric Oxide"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1093\/cvr\/cvy038","article-title":"Multiple Common Comorbidities Produce Left Ventricular Diastolic Dysfunction Associated with Coronary Microvascular Dysfunction, Oxidative Stress, and Myocardial Stiffening","volume":"114","author":"Sorop","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/cvr\/cvy095","article-title":"Modelling the Complexity of Heart Failure with Preserved Ejection Fraction","volume":"114","author":"Shah","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jacc.2013.02.092","article-title":"A Novel Paradigm for Heart Failure With Preserved Ejection Fraction","volume":"62","author":"Paulus","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Suvorava, T., Metry, S., Pick, S., and Kojda, G. (2022). Alterations in Endothelial Nitric Oxide Synthase Activity and Their Relevance to Blood Pressure. Biochem. Pharmacol., 205.","DOI":"10.1016\/j.bcp.2022.115256"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Gorabi, A.M., Kiaie, N., Hajighasemi, S., Banach, M., Penson, P.E., Jamialahmadi, T., and Sahebkar, A. (2019). Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications. J. Clin. Med., 8.","DOI":"10.3390\/jcm8122051"},{"key":"ref_109","first-page":"606","article-title":"Nifedipine and Diltiazem but Not Verapamil Up-Regulate Endothelial Nitric-Oxide Synthase Expression","volume":"292","author":"Ding","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Daiber, A., Xia, N., Steven, S., Oelze, M., Hanf, A., Kr\u00f6ller-Sch\u00f6n, S., M\u00fcnzel, T., and Li, H. (2019). New Therapeutic Implications of Endothelial Nitric Oxide Synthase (ENOS) Function\/Dysfunction in Cardiovascular Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010187"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Rodrigues-Krause, J., Krause, M., Rocha, I., Umpierre, D., and Fayh, A. (2018). Association of L-Arginine Supplementation with Markers of Endothelial Function in Patients with Cardiovascular or Metabolic Disorders: A Systematic Review and Meta-Analysis. Nutrients, 11.","DOI":"10.3390\/nu11010015"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1002\/clc.20616","article-title":"Oral L-Arginine Supplementation in Acute Myocardial Infarction Therapy: A Meta-Analysis of Randomized Controlled Trials","volume":"32","author":"Sun","year":"2009","journal-title":"Clin. Cardiol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1001\/jama.295.1.58","article-title":"L-Arginine Therapy in Acute Myocardial Infarction","volume":"295","author":"Schulman","year":"2006","journal-title":"JAMA"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.niox.2016.02.006","article-title":"Effect of Asymmetric Dimethylarginine (ADMA) on Heart Failure Development","volume":"54","author":"Liu","year":"2016","journal-title":"Nitric Oxide"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1015908","DOI":"10.1155\/2020\/1015908","article-title":"Intraplatelet L-Arginine-Nitric Oxide Metabolic Pathway: From Discovery to Clinical Implications in Prevention and Treatment of Cardiovascular Disorders","volume":"2020","author":"Gawrys","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.pharmthera.2007.08.001","article-title":"L-Arginine Transporters in Cardiovascular Disease: A Novel Therapeutic Target","volume":"116","author":"Willems","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1161\/01.ATV.0000258946.55438.0e","article-title":"Oral Administration of Tetrahydrobiopterin Slows the Progression of Atherosclerosis in Apolipoprotein E-Knockout Mice","volume":"27","author":"Hattori","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1161\/ATVBAHA.111.226456","article-title":"Tetrahydrobiopterin Deficiency and Nitric Oxide Synthase Uncoupling Contribute to Atherosclerosis Induced by Disturbed Flow","volume":"31","author":"Li","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1161\/CIRCULATIONAHA.107.737031","article-title":"Reversal of Cardiac Hypertrophy and Fibrosis From Pressure Overload by Tetrahydrobiopterin","volume":"117","author":"Moens","year":"2008","journal-title":"Circulation"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ijcard.2013.08.075","article-title":"Myocardial Protection by Co-Administration of l-Arginine and Tetrahydrobiopterin during Ischemia and Reperfusion","volume":"169","author":"Tratsiakovich","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1161\/01.CIR.102.18.2172","article-title":"Endothelial Dysfunction of Coronary Resistance Arteries Is Improved by Tetrahydrobiopterin in Atherosclerosis","volume":"102","author":"Tiefenbacher","year":"2000","journal-title":"Circulation"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1161\/CIRCULATIONAHA.111.038919","article-title":"Systemic and Vascular Oxidation Limits the Efficacy of Oral Tetrahydrobiopterin Treatment in Patients With Coronary Artery Disease","volume":"125","author":"Cunnington","year":"2012","journal-title":"Circulation"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1161\/STROKEAHA.114.005937","article-title":"Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL","volume":"45","author":"Campolo","year":"2014","journal-title":"Stroke"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1161\/HYPERTENSIONAHA.107.103523","article-title":"Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite","volume":"51","author":"Webb","year":"2008","journal-title":"Hypertension"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.nutres.2020.03.002","article-title":"A Systemic Review on the Antioxidant and Anti-Inflammatory Effects of Resveratrol, Curcumin, and Dietary Nitric Oxide Supplementation on Human Cardiovascular Health","volume":"78","author":"Banez","year":"2020","journal-title":"Nutr. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.niox.2020.01.006","article-title":"Mechanisms of the Protective Effects of Nitrate and Nitrite in Cardiovascular and Metabolic Diseases","volume":"96","author":"Liu","year":"2020","journal-title":"Nitric Oxide"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1093\/cvr\/cvab240","article-title":"Cyclic GMP Modulating Drugs in Cardiovascular Diseases: Mechanism-Based Network Pharmacology","volume":"118","author":"Petraina","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2017.11.003","article-title":"Inorganic Nitrite and Nitrate in Cardiovascular Therapy: A Better Alternative to Organic Nitrates as Nitric Oxide Donors?","volume":"102","author":"Daiber","year":"2018","journal-title":"Vasc. Pharmacol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1056\/NEJMoa1510774","article-title":"Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction","volume":"373","author":"Redfield","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1161\/CIRCULATIONAHA.107.717702","article-title":"Improvement in Left Ventricular Remodeling by the Endothelial Nitric Oxide Synthase Enhancer AVE9488 After Experimental Myocardial Infarction","volume":"118","author":"Fraccarollo","year":"2008","journal-title":"Circulation"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s00395-009-0014-6","article-title":"Enhancement of the Endothelial NO Synthase Attenuates Experimental Diastolic Heart Failure","volume":"104","author":"Westermann","year":"2009","journal-title":"Basic. Res. Cardiol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.abb.2015.02.020","article-title":"AVE 3085, a Novel Endothelial Nitric Oxide Synthase Enhancer, Attenuates Cardiac Remodeling in Mice through the Smad Signaling Pathway","volume":"570","author":"Chen","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/eurjhf\/hfp005","article-title":"Inhibition of Platelet Activation in Rats with Severe Congestive Heart Failure by a Novel Endothelial Nitric Oxide Synthase Transcription Enhancer","volume":"11","author":"Fraccarollo","year":"2009","journal-title":"Eur. J. Heart Fail."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1111\/j.1476-5381.2011.01308.x","article-title":"AVE3085, an Enhancer of Endothelial Nitric Oxide Synthase, Restores Endothelial Function and Reduces Blood Pressure in Spontaneously Hypertensive Rats","volume":"163","author":"Yang","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1093\/cvr\/cvr233","article-title":"Endothelial Nitric Oxide Synthase Enhancer Reduces Oxidative Stress and Restores Endothelial Function in Db\/Db Mice","volume":"92","author":"Cheang","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.carpath.2007.02.007","article-title":"Inhibition of TGF-\u03921 Signaling by ENOS Gene Transfer Improves Ventricular Remodeling after Myocardial Infarction through Angiogenesis and Reduction of Apoptosis","volume":"16","author":"Chen","year":"2007","journal-title":"Cardiovasc. Pathol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1177\/1358863X09360264","article-title":"Adenoviral-Mediated Overexpression of DDAH Improves Vascular Tone Regulation","volume":"15","author":"Torondel","year":"2010","journal-title":"Vasc. Med."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1096\/fj.02-0668fje","article-title":"Protection against Lipopolysaccharide-induced Endothelial Dysfunction in Resistance and Conduit Vasculature of INOS Knockout Mice","volume":"17","author":"Chauhan","year":"2003","journal-title":"FASEB J."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0167-5273(95)02385-A","article-title":"Involvement of Inducible Nitric Oxide Synthase in the Inflammatory Process of Myocardial Infarction","volume":"50","author":"Wildhirt","year":"1995","journal-title":"Int. J. Cardiol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1161\/01.RES.85.9.829","article-title":"Cytokine-Mediated Apoptosis in Cardiac Myocytes","volume":"85","author":"Arstall","year":"1999","journal-title":"Circ. Res."},{"key":"ref_141","first-page":"5732956","article-title":"The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor","volume":"2020","author":"Schipani","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Dubois-deruy, E., Peugnet, V., Turkieh, A., and Pinet, F. (2020). Oxidative Stress in Cardiovascular Diseases. Antioxidants, 9.","DOI":"10.3390\/antiox9090864"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1080\/15216540310001628681","article-title":"Mitochondrial Nitric-Oxide Synthase: Role in Pathophysiology","volume":"55","author":"Haynes","year":"2003","journal-title":"IUBMB Life"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.niox.2019.04.005","article-title":"The Effect of Nitric Oxide on Mitochondrial Respiration","volume":"88","author":"Poderoso","year":"2019","journal-title":"Nitric Oxide"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.celrep.2019.06.018","article-title":"Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation","volume":"28","author":"Bailey","year":"2019","journal-title":"Cell Rep."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/nrm2434","article-title":"Cytochrome c: Functions beyond Respiration","volume":"9","author":"Ow","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1161\/CIRCULATIONAHA.119.043578","article-title":"S-Nitrosylation of Histone Deacetylase 2 by Neuronal Nitric Oxide Synthase as a Mechanism of Diastolic Dysfunction","volume":"143","author":"Yoon","year":"2021","journal-title":"Circulation"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1056\/NEJMoa2206286","article-title":"Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction","volume":"387","author":"Solomon","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.1093\/eurheartj\/ehab420","article-title":"Effects of Canagliflozin on Human Myocardial Redox Signalling: Clinical Implications","volume":"42","author":"Kondo","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1016\/j.jacc.2020.03.051","article-title":"Physiological Stratification of Patients With Angina Due to Coronary Microvascular Dysfunction","volume":"75","author":"Rahman","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"4431","DOI":"10.1093\/eurheartj\/ehab653","article-title":"Untangling the Pathophysiologic Link between Coronary Microvascular Dysfunction and Heart Failure with Preserved Ejection Fraction","volume":"42","author":"Sinha","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"430","DOI":"10.3892\/etm.2022.11357","article-title":"Myocardial Ischemia\/Reperfusion Injury: Mechanisms of Injury and Implications for Management (Review)","volume":"23","author":"He","year":"2022","journal-title":"Exp. Ther. Med."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41569-020-0403-y","article-title":"Myocardial Ischaemia\u2013Reperfusion Injury and Cardioprotection in Perspective","volume":"17","author":"Heusch","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1096\/fj.02-1208fje","article-title":"Up-regulation of Cardiac Nitric Oxide Synthase 1-derived Nitric Oxide after Myocardial Infarction in Senescent Rats","volume":"17","author":"Damy","year":"2003","journal-title":"FASEB J."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"8364848","DOI":"10.1155\/2018\/8364848","article-title":"The Dual Role of Inducible Nitric Oxide Synthase in Myocardial Ischemia\/Reperfusion Injury: Friend or Foe?","volume":"2018","author":"Yu","year":"2018","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00414-019-02051-y","article-title":"Increased Inducible Nitric Oxide Synthase (INOS) Expression in Human Myocardial Infarction","volume":"134","author":"Wilmes","year":"2020","journal-title":"Int. J. Legal Med."},{"key":"ref_157","first-page":"432","article-title":"Inhibition of Nitric Oxide Synthesis Protects the Isolated Working Rabbit Heart from Ischaemia-Reperfusion Injury","volume":"30","author":"Schulz","year":"1995","journal-title":"Cardiovasc. Res."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/S0008-6363(96)00254-4","article-title":"Generation of Peroxynitrite Contributes to Ischemia-Reperfusion Injury in Isolated Rat Hearts","volume":"33","author":"Yasmin","year":"1997","journal-title":"Cardiovasc. Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1006\/bbrc.1993.1809","article-title":"Inhibition of Nitric Oxide Limits Infarct Size in the in Situ Rabbit Heart","volume":"194","author":"Patel","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1161\/01.CIR.0000124489.46660.2E","article-title":"Metabolic and Functional Protection by Selective Inhibition of Nitric Oxide Synthase 2 During Ischemia-Reperfusion in Isolated Perfused Hearts","volume":"109","author":"Ramasamy","year":"2004","journal-title":"Circulation"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1124\/jpet.106.102160","article-title":"Chronic \u03b2-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia\/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress","volume":"318","author":"Hu","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1161\/01.CIR.101.12.1358","article-title":"L-NMMA (a Nitric Oxide Synthase Inhibitor) Is Effective in the Treatment of Cardiogenic Shock","volume":"101","author":"Cotter","year":"2000","journal-title":"Circulation"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/S0195-668X(03)00193-3","article-title":"LINCS: L-NAME (a NO Synthase Inhibitor) In the Treatment of Refractory Cardiogenic Shock A Prospective Randomized Study","volume":"24","author":"Cotter","year":"2003","journal-title":"Eur. Heart J."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1093\/eurheartj\/ehm075","article-title":"Effect of Nitric Oxide Synthase Inhibition on Haemodynamics and Outcome of Patients with Persistent Cardiogenic Shock Complicating Acute Myocardial Infarction: A Phase II Dose-Ranging Study","volume":"28","author":"Dzavik","year":"2007","journal-title":"Eur. Heart J."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"The TRIUMPH Investigators (2007). Effect of Tilarginine Acetate in Patients With Acute Myocardial Infarction and Cardiogenic Shock. JAMA, 297, 1657.","DOI":"10.1001\/jama.297.15.joc70035"},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Shen, Z., Xiang, M., Chen, C., Ding, F., Wang, Y., Shang, C., Xin, L., Zhang, Y., and Cui, X. (2022). Glutamate Excitotoxicity: Potential Therapeutic Target for Ischemic Stroke. Biomed. Pharmacother., 151.","DOI":"10.1016\/j.biopha.2022.113125"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.3389\/fnins.2019.01036","article-title":"Potential Neuroprotective Treatment of Stroke: Targeting Excitotoxicity, Oxidative Stress, and Inflammation","volume":"13","author":"Yang","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"579953","DOI":"10.3389\/fnins.2020.579953","article-title":"Excitotoxicity: Still Hammering the Ischemic Brain in 2020","volume":"14","author":"Choi","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1007\/s12264-023-01060-7","article-title":"NNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story","volume":"39","author":"Zhu","year":"2023","journal-title":"Neurosci. Bull."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.pneurobio.2013.11.006","article-title":"Excitotoxicity and Stroke: Identifying Novel Targets for Neuroprotection","volume":"115","author":"Lai","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1523\/JNEUROSCI.13-06-02651.1993","article-title":"Mechanisms of Nitric Oxide-Mediated Neurotoxicity in Primary Brain Cultures","volume":"13","author":"Dawson","year":"1993","journal-title":"J. Neurosci."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"6368","DOI":"10.1073\/pnas.88.14.6368","article-title":"Nitric Oxide Mediates Glutamate Neurotoxicity in Primary Cortical Cultures","volume":"88","author":"Dawson","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1523\/JNEUROSCI.16-08-02479.1996","article-title":"Resistance to Neurotoxicity in Cortical Cultures from Neuronal Nitric Oxide Synthase-Deficient Mice","volume":"16","author":"Dawson","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1126\/science.7522345","article-title":"Effects of Cerebral Ischemia in Mice Deficient in Neuronal Nitric Oxide Synthase","volume":"265","author":"Huang","year":"1994","journal-title":"Science"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S1474-4422(12)70225-9","article-title":"Safety and Efficacy of NA-1 in Patients with Iatrogenic Stroke after Endovascular Aneurysm Repair (ENACT): A Phase 2, Randomised, Double-Blind, Placebo-Controlled Trial","volume":"11","author":"Hill","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/S0140-6736(20)30258-0","article-title":"Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke (ESCAPE-NA1): A Multicentre, Double-Blind, Randomised Controlled Trial","volume":"395","author":"Hill","year":"2020","journal-title":"Lancet"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"63","DOI":"10.2176\/nmc.41.63","article-title":"Time Course of Expression of Three Nitric Oxide Synthase Isoforms After Transient Middle Cerebral Artery Occlusion in Rats","volume":"41","author":"NIWA","year":"2001","journal-title":"Neurol. Med. Chir."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/378383a0","article-title":"Behavioural Abnormalities in Male Mice Lacking Neuronal Nitric Oxide Synthase","volume":"378","author":"Nelson","year":"1995","journal-title":"Nature"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"26677","DOI":"10.1016\/S0021-9258(18)47072-X","article-title":"Potent and Selective Inhibition of Human Nitric Oxide Synthases. Selective Inhibition of Neuronal Nitric Oxide Synthase by S-Methyl-L-Thiocitrulline and S-Ethyl-L-Thiocitrulline","volume":"269","author":"Furfine","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_180","first-page":"1273","article-title":"Synthesis, in Vivo Evaluation and PET Study of a Carbon-11-Labeled Neuronal Nitric Oxide Synthase (NNOS) Inhibitor S-Methyl-L-Thiocitrulline","volume":"38","author":"Zhang","year":"1997","journal-title":"J. Nucl. Med."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.expneurol.2004.05.029","article-title":"Agmatine Reduces Infarct Area in a Mouse Model of Transient Focal Cerebral Ischemia and Protects Cultured Neurons from Ischemia-like Injury","volume":"189","author":"Kim","year":"2004","journal-title":"Exp. Neurol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.neuro.2019.05.001","article-title":"Neuroprotective Offerings by Agmatine","volume":"73","author":"Kotagale","year":"2019","journal-title":"Neurotoxicology"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1179\/016164107X208103","article-title":"Agmatine Inhibits Matrix Metalloproteinase-9 via Endothelial Nitric Oxide Synthase in Cerebral Endothelial Cells","volume":"29","author":"Yang","year":"2007","journal-title":"Neurol. Res."},{"key":"ref_184","first-page":"780","article-title":"Protective Effect of Agmatine on a Reperfusion Model after Transient Cerebral Ischemia: Temporal Evolution on Perfusion MR Imaging and Histopathologic Findings","volume":"27","author":"Kim","year":"2006","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1203\/00006450-200210000-00023","article-title":"Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats","volume":"52","author":"Feng","year":"2002","journal-title":"Pediatr. Res."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s13063-019-3965-4","article-title":"Efficacy of Ronopterin (VAS203) in Patients with Moderate and Severe Traumatic Brain Injury (NOSTRA Phase III Trial): Study Protocol of a Confirmatory, Placebo-Controlled, Randomised, Double Blind, Multi-Centre Study","volume":"21","author":"Tegtmeier","year":"2020","journal-title":"Trials"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1111\/bcp.13870","article-title":"Effects of the Nitric Oxide Synthase Inhibitor Ronopterin (VAS203) on Renal Function in Healthy Volunteers","volume":"85","author":"Ott","year":"2019","journal-title":"Br. J. Clin. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15200\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:07:08Z","timestamp":1760130428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,15]]},"references-count":187,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015200"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015200","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,15]]}}}