A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia–reperfusion in the mouse heart

• Published in: Scientific reports Vol. 11; no. 1; p. 11970
• Main Authors: Szekeres, Ferenc L. M., Walum, Erik, Wikström, Per, Arner, Anders
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308; 692/4019; 692/699; 692/700; Animals; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Basic Medicine; Cardiac and Cardiovascular Systems; Cardiomyocytes; Cell and Molecular Biology; Cell- och molekylärbiologi; Clinical Medicine; Contraction; CYBB protein; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Female; Heart; Humanities and Social Sciences; Humans; Ischemia; Kardiologi; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Inbred C57BL; multidisciplinary; Muscle contraction; Myocardial Reperfusion Injury - drug therapy; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; NAD(P)H oxidase; NADPH Oxidase 2 - metabolism; NADPH Oxidase 4 - metabolism; NOX4 protein; Oxidation-Reduction; Oxidative Stress; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reperfusion; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Translational Medicine TRIM; Translationell medicin TRIM
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-91575-8

The NADPH oxidase enzymes Nox2 and 4, are important generators of Reactive oxygen species (ROS). These enzymes are abundantly expressed in cardiomyocytes and have been implicated in ischemia–reperfusion injury. Previous attempts with full inhibition of their activity using genetically modified animals have shown variable results, suggesting that a selective and graded inhibition could be a more relevant approach. We have, using chemical library screening, identified a new compound (GLX481304) which inhibits Nox 2 and 4 (with IC 50 values of 1.25 µM) without general antioxidant effects or inhibitory effects on Nox 1. The compound inhibits ROS production in isolated mouse cardiomyocytes and improves cardiomyocyte contractility and contraction of whole retrogradely (Langendorff) perfused hearts after a global ischemia period. We conclude that a pharmacological and partial inhibition of ROS production by inhibition of Nox 2 and 4 is beneficial for recovery after ischemia reperfusion and might be a promising venue for treatment of ischemic injury to the heart.