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

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.

NOX4 inhibition promotes the remodeling of dystrophic muscle

“…Thus, implementation of GKT831, and/or other NOX4-inhibiting molecules, for the treatment of fibrotic conditions in more regenerative organs, including skeletal muscle, is anticipated to have a more optimistic outcome. While the data of the current study demonstrate NOX4 is an effective therapeutic target in dystrophic muscle by targeting interstitial components of the disease, a dual NOX2/4 inhibitor, such as that recently described by Szekeres et al ( 59 ), may offer additional benefits by also targeting NOX2, which drives dysfunction in muscle fibers ( 41 , 42 ). Furthermore, such a strategy may offer added cardioprotection, as both NOX2 and NOX4 are capable of contributing to cardiomyocyte dysfunction and cardiac pathology ( 59 – 62 ).…”

The Role of Interventional Irisin on Heart Molecular Physiology

“…Interestingly, it was reported that cardiac and systematic knockdown of Nox4 significantly reduced infarct size and area at risk after the ischemia–reperfusion challenge [ 37 ]. Inhibition of Nox4, which is expressed in cardiomyocytes by a selective inhibitor (GLX481304), reduced the generation of free reactive oxygen species in mouse cardiac muscle and enhanced the cell contractile function, improving the whole heart after a hypoxic/ischemic–reperfusion challenge [ 38 ].…”

The loss of pancreatic islet NADPH oxidase (NOX)2 improves islet transplantation

“…However, targeting mitochondrial ROS with antioxidants may be challenging, as mitochondria derived-H 2 O 2 was shown to be an obligatory signal for glucose-induced insulin secretion [ 74 ]. NOXs stand out as their sole function is to produce ROS, which qualifies NOXs as the main potential drug-target candidates in diseases [ 15 , 75 , 76 ]. Recently, the WHO approved NOXs inhibitors, such as Setanaxib, as a new therapeutic class, which has significant potential in fibrotic, inflammatory, neurodegenerative, and oncology disorders [ 77 ].…”