Treatment with the Nox1/4 inhibitor Setanaxib ameliorates cardiac function in mouse models of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is caused by mutations in dystrophin, leading to degeneration and weakness of skeletal and cardiac muscle. Despite great progress in the development of gene replacement therapies, DMD remains a devastating disease. In our recent work, we demonstrated that loss of the cardiac Isl1-interacting protein (CIP), which interacts with dystrophin in sarcolemma of cardiomyocytes, accelerates the progression of dystrophic cardiomyopathy and identified Nox4 as one of the downstream mediators of this process. Here, we report that setanaxib, a Nox1/4 inhibitor, protected the heart of CIP/Mdx double knockout (dKO) mice from heart failure; significantly, this compound also reduced cardiac fibrosis and protected against heart failure in Mdx/Utrn dKO mouse. At a molecular level, Nox1/4 inhibition reduced the expression of genes associated with cardiomyopathy in these animals. Further transcriptomic analysis of the hearts treated with setanaxib revealed an enrichment in genes associated with fatty acid metabolism, oxidative phosphorylation, and protein binding, while genes related to epithelial-mesenchymal transition were downregulated. Collectively, these findings suggest that oxidative stress plays a key role in development of myocardial fibrosis and heart failure caused by dystrophin deficiency and suggest that Nox1/4 inhibitor treatment could be a novel therapy to treat DMD-associated cardiomyopathy.