2. Academic Validation
  3. A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia-reperfusion in the mouse heart

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

  • Sci Rep. 2021 Jun 7;11(1):11970. doi: 10.1038/s41598-021-91575-8.
Ferenc L M Szekeres 1 2,  Erik Walum 3,  Per Wikström 3,  Anders Arner 4 5
Affiliations

Affiliations

  • 1 Division of Genetic Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, von Eulers Väg 8, 17177, Stockholm, Sweden. [email protected].
  • 2 Division of Biomedicine, Department of Health and Education, University of Skövde, Högskolevägen 1, 541 28, Skövde, Sweden. [email protected].
  • 3 Glucox Biotech AB, Frälsegårdsvägen 8, 179 97, Färentuna, Sweden.
  • 4 Division of Genetic Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, von Eulers Väg 8, 17177, Stockholm, Sweden.
  • 5 Department of Clinical Sciences Lund, Thoracic Surgery, Lund University, c/o Igelösa Life Science AB Igelösa 373, 225 94, Lund, Sweden.
PMID: 34099836 DOI: 10.1038/s41598-021-91575-8
Abstract

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 IC50 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.

Figures
Products