Nox4 inhibitor treatment 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 the skeletal and cardiac muscles. Despite numerous efforts in developing therapies for this devastating disease, DMD remains a fatal disease. Our recent study showed that loss of the cardiac Isl1-interacting protein (CIP), which interacts with dystrophin in sarcolemma of cardiomyocytes, accelerates the progression of dystrophic cardiomyopathy. We 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 and reduced cardiac fibrosis. Similarly, Setanaxib treatment exhibited lower cardiac fibrosis and protection against heart failure in Mdx/Utrn dKO mouse, another murine model for dystrophic cardiomyopathy. Additionally, treatment with Nox4 inhibitor reduced the expression of cardiomyopathy genes in dystrophic mice. Interestingly, transcriptomic analysis of the hearts from Mdx/Utrn dKO mice treated with Nox4 inhibitor reveals an enrichment of genes associated with fatty acid metabolism, oxidative phosphorylation, and protein binding, while genes related to inflammation and epithelial-mesenchymal transition were downregulated. Consistent with these results, we found increased expression of Pgc1a and Tcap in the hearts of Mdx/Utrn dKO mice treated with Nox 4 inhibitor, and reduced expression of Mcp1. Collectively, these findings suggest that Nox4 plays a key role in development of myocardial fibrosis and heart failure caused by dystrophin deficiency, and suggest that Nox4 inhibition could be a potential novel therapy to alleviate cardiomyopathy in DMD patients.