Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA.
Life Sci Alliance. 2019 Feb 11;2(1). doi: 10.26508/lsa.201800186. Print 2019 Feb.
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.
心肌病是杜氏肌营养不良症死亡的主要原因。在这里，我们发现盐皮质激素受体 (MR) 和糖皮质激素受体 (GR) 可以共享共同的配体，但在营养不良的心脏和骨骼肌病理生理学中发挥着不同的作用。对它们配体结构的比较表明，首类药物沃莫罗龙的Δ9,11 修饰使其能够避免与保守的受体残基 (N770/N564) 相互作用，否则这会激活两种受体的转录因子特性。报告基因检测表明，沃莫罗龙和依普利酮是 MR 拮抗剂，而泼尼松龙是 MR 激动剂。巨噬细胞、心肌细胞和 CRISPR 敲除成肌细胞表明，沃莫罗龙也是一种分离的 GR 配体，可抑制炎症，与泼尼松龙和 GR 特异性地拉考沙胺相比，安全性提高。在小鼠中，醛固酮增多症会激活 MR 驱动的高血压和肾脏表型。我们发现，遗传型肌营养不良蛋白缺失为杜氏肌营养不良症模型小鼠的 MR 介导的心肌病提供了第二次打击，因为醛固酮会加重纤维化、质量和功能障碍表型。沃莫罗龙成功地预防了 MR 激活的表型，而泼尼松龙则激活了负性 MR 和 GR 效应。总之，沃莫罗龙靶向双重核受体，可提高安全性来治疗炎症和心肌病。
