RT Journal Article
SR Electronic
T1 Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800186
DO 10.26508/lsa.201800186
VO 2
IS 1
A1 Christopher R Heier
A1 Qing Yu
A1 Alyson A Fiorillo
A1 Christopher B Tully
A1 Asya Tucker
A1 Davi A Mazala
A1 Kitipong Uaesoontrachoon
A1 Sadish Srinivassane
A1 Jesse M Damsker
A1 Eric P Hoffman
A1 Kanneboyina Nagaraju
A1 Christopher F Spurney
YR 2019
UL https://www.life-science-alliance.org/content/2/1/e201800186.abstract
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.