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.
Highlights
The NADPH oxidase enzymes NADPH oxidases (Nox)[2] and 4, are important generators of Reactive oxygen species (ROS)
To address the question whether the effects of GLX481304 on reactive oxygen species production in the cardiomyocytes exposed to hypoxia-reoxygenation was accompanied by improved contractile performance we examined shortening responses and Ca2+ transients in isolated cardiomyocytes exposed to the hypoxia-reoxygenation challenge
Generation of Reactive Oxygen Species (ROS) via Nox enzymes is an important event in ischemia–reperfusion injury in the h eart[3], but the detailed pathophysiological impact of Nox activity is not fully understood, and in some aspects controversial: Significantly decreased injury following myocardial ischemia/reperfusion has been reported in Nox 1 and Nox 2 knockout mice, but not in Nox 4 deficient a nimals[33]
Summary
The NADPH oxidase enzymes Nox[2] 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. The heart is an aerobic muscle—its contractile function is critically dependent on a continuous blood flow and an adequate supply of oxygen throughout life These important processes are threatened in several common chronic diseases, associated with alterations in the coronary vessels, e.g., in atherosclerosis/ischemic heart disease which affects a large number of individuals and is one of the main causes of sudden death worldwide[1,2]. In this study we have developed a new specific small molecule Nox2/Nox[4] inhibitor (GLX481304), and show, using isolated cardiomyocytes and perfused whole hearts from mouse that the compound inhibits ROS production in the cardiac cells and improves contractility after an ischemia–reperfusion challenge
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