Macrophage Mineralocorticoid Receptor Is a Pleiotropic Modulator of Myocardial Infarct Healing
Macrophage Mineralocorticoid Receptor Is a Pleiotropic Modulator of Myocardial Infarct Healing
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DOI：
10.1161/hypertensionaha.118.12162
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发表时间：
2019-01-01
期刊：
影响因子：
8.3
通讯作者：
Bauersachs, Johann
中科院分区：
文献类型：
--
作者：
Fraccarollo, Daniela;Thomas, Svenja;Bauersachs, Johann
心肌梗死（MI）是全球范围内的主要死亡原因。在这里，我们确定了巨噬细胞MR（盐皮质激素受体）作为一个重要的致病球员在心肌梗死后的心脏伤口修复。左冠状动脉结扎后7天，与WT（野生型）对照组相比，髓系细胞限制性MR缺陷小鼠显示出改善的心脏功能和重塑，与增强的梗死新生血管形成和瘢痕成熟相关。心脏驻留和梗死巨噬细胞的基因表达谱显示，MR缺失驱动缺血微环境中的巨噬细胞分化为M1/M2范式以外的表型，并调节控制伤口愈合和组织修复的多个相关因素。机制和功能的数据表明，灭活的巨噬细胞MR促进心肌梗死愈合，通过增强中性粒细胞的吞噬，抑制自由基的形成，和成纤维细胞活化状态的调制。至关重要的是，在MI发作时单次给予RU 28318或含依普利酮的脂质体，将MR拮抗剂靶向递送至巨噬细胞，改善了愈合反应并防止心脏重塑和功能恶化，为心脏修复提供了有效且独特的治疗策略。
Myocardial infarction (MI) is a major cause of death worldwide. Here, we identify the macrophage MR (mineralocorticoid receptor) as a crucial pathogenic player in cardiac wound repair after MI. Seven days after left coronary artery ligation, mice with myeloid cell-restricted MR deficiency compared with WT (wild type) controls displayed improved cardiac function and remodeling associated with enhanced infarct neovascularization and scar maturation. Gene expression profiling of heart-resident and infarct macrophages revealed that MR deletion drives macrophage differentiation in the ischemic microenvironment toward a phenotype outside the M1/M2 paradigm, with regulation of multiple interrelated factors controlling wound healing and tissue repair. Mechanistic and functional data suggest that inactivation of the macrophage MR promotes myocardial infarct healing through enhanced efferocytosis of neutrophils, the suppression of free radical formation, and the modulation of fibroblast activation state. Crucially, targeted delivery of MR antagonists to macrophages, with a single administration of RU28318 or eplerenone-containing liposomes at the onset of MI, improved the healing response and protected against cardiac remodeling and functional deterioration, offering an effective and unique therapeutic strategy for cardiac repair.