PT - JOURNAL ARTICLE AU - Christopher R Heier AU - Qing Yu AU - Alyson A Fiorillo AU - Christopher B Tully AU - Asya Tucker AU - Davi A Mazala AU - Kitipong Uaesoontrachoon AU - Sadish Srinivassane AU - Jesse M Damsker AU - Eric P Hoffman AU - Kanneboyina Nagaraju AU - Christopher F Spurney TI - Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy AID - 10.26508/lsa.201800186 DP - 2019 Feb 01 TA - Life Science Alliance PG - e201800186 VI - 2 IP - 1 4099 - https://www.life-science-alliance.org/content/2/1/e201800186.short 4100 - https://www.life-science-alliance.org/content/2/1/e201800186.full SO - Life Sci. Alliance2019 Feb 01; 2 AB - Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle pathophysiology. Comparisons of their ligand structures indicate that the Δ9,11 modification of the first-in-class drug vamorolone enables it to avoid interaction with a conserved receptor residue (N770/N564), which would otherwise activate transcription factor properties of both receptors. Reporter assays show that vamorolone and eplerenone are MR antagonists, whereas prednisolone is an MR agonist. Macrophages, cardiomyocytes, and CRISPR knockout myoblasts show vamorolone is also a dissociative GR ligand that inhibits inflammation with improved safety over prednisone and GR-specific deflazacort. In mice, hyperaldosteronism activates MR-driven hypertension and kidney phenotypes. We find that genetic dystrophin loss provides a second hit for MR-mediated cardiomyopathy in Duchenne muscular dystrophy model mice, as aldosterone worsens fibrosis, mass and dysfunction phenotypes. Vamorolone successfully prevents MR-activated phenotypes, whereas prednisolone activates negative MR and GR effects. In conclusion, vamorolone targets dual nuclear receptors to treat inflammation and cardiomyopathy with improved safety.