Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy
Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy
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DOI：
10.1093/hmg/ddw331
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发表时间：
2016-12-01
影响因子：
3.5
通讯作者：
Rafael-Fortney, Jill A.
中科院分区：
文献类型：
--
作者：
Chadwick, Jessica A.;Swager, Sarah A.;Rafael-Fortney, Jill A.
fda批准的矿皮质激素受体（MR）拮抗剂用于治疗心力衰竭。我们最近在杜氏肌营养不良小鼠模型中证明了MR拮抗剂对骨骼肌和心脏的疗效，并且骨骼肌中存在矿化皮质激素受体并具有功能。本研究的目的是阐明MR拮抗剂对营养不良骨骼肌疗效的潜在机制。我们首次证明，聚集在营养不良骨骼肌受损区域的浸润性骨髓细胞有能力产生MR的天然配体醛固酮，过量的醛固酮已知会加剧组织损伤。与对照组相比，从营养不良肌肉分离的白细胞中醛固酮合成酶蛋白水平升高，尽管营养不良骨骼肌的局部醛固酮水平正常，但仍升高。所有编码醛固酮合成途径中酶的基因都在肌源性白细胞中表达。11 β - hsd2，一种使糖皮质激素失活以增加醛固酮MR选择性的酶，在营养不良的肌肉组织中也会增加。这些结果，再加上拮抗剂的临床前疗效，表明MR激活超出了生理需要，可能导致肌肉萎缩症的病理。这项研究为骨髓细胞对肌营养不良病理的已知贡献提供了新的机制见解。这是骨髓细胞产生醛固酮能力的第一篇报道，可能对多种急性损伤和慢性炎症疾病有意义，其中MR拮抗剂可能是治疗性的。
FDA-approved mineralocorticoid receptor (MR) antagonists are used to treat heart failure. We have recently demonstrated efficacy of MR antagonists for skeletal muscles in addition to heart in Duchenne muscular dystrophy mouse models and that mineralocorticoid receptors are present and functional in skeletal muscles. The goal of this study was to elucidate the underlying mechanisms of MR antagonist efficacy on dystrophic skeletal muscles. We demonstrate for the first time that infiltrating myeloid cells clustered in damaged areas of dystrophic skeletal muscles have the capacity to produce the natural ligand of MR, aldosterone, which in excess is known to exacerbate tissue damage. Aldosterone synthase protein levels are increased in leukocytes isolated from dystrophic muscles compared with controls and local aldosterone levels in dystrophic skeletal muscles are increased, despite normal circulating levels. All genes encoding enzymes in the pathway for aldosterone synthesis are expressed in muscle-derived leukocytes. 11 beta-HSD2, the enzyme that inactivates glucocorticoids to increase MR selectivity for aldosterone, is also increased in dystrophic muscle tissues. These results, together with the demonstrated preclinical efficacy of antagonists, suggest MR activation is in excess of physiological need and likely contributes to the pathology of muscular dystrophy. This study provides new mechanistic insight into the known contribution of myeloid cells to muscular dystrophy pathology. This first report of myeloid cells having the capacity to produce aldosterone may have implications for a wide variety of acute injuries and chronic diseases with inflammation where MR antagonists may be therapeutic.