Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice
Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice
复制标题
DOI：
10.1172/jci41080
复制
发表时间：
2010-09-01
影响因子：
15.9
通讯作者：
Mortensen, Richard M.
中科院分区：
文献类型：
--
作者：
Usher, Michael G.;Duan, Sheng Zhong;Mortensen, Richard M.
类固醇激素醛固酮是一种盐皮质激素受体（MR）激动剂，其过量与炎症增加和心血管疾病风险有关。MR拮抗剂在体内具有心脏保护作用，有证据表明它们部分通过醛固酮非依赖性机制介导这些作用。在这里，我们已经表明，骨髓细胞的MR是必要的有效的经典巨噬细胞活化的促炎细胞因子。来自骨髓细胞中缺乏MR的小鼠（本文称为MyMRKO小鼠）的巨噬细胞表现出交替激活的转录谱。在体外，MR缺乏与交替激活巨噬细胞的诱导剂（例如，IL-4和PPAR γ和糖皮质激素受体的激动剂）协同作用，以增强交替激活。在体内，巨噬细胞中的MR缺乏模仿MR拮抗剂的作用，并保护免受L-NAME/Ang II引起的心脏肥大、纤维化和血管损伤。在用L-NAME/Ang II治疗MyMRKO小鼠期间观察到血压和心率增加以及昼夜节律变化减少。我们的结论是，骨髓MR是一个重要的控制点，在巨噬细胞极化和功能的MR骨髓细胞可能代表了一个保守的祖先MR功能，整合在一个转录网络与过氧化物酶体增殖物激活受体γ和糖皮质激素受体。此外，髓样MR对于血压控制以及小鼠心脏和主动脉中的肥大和纤维化反应至关重要。
Inappropriate excess of the steroid hormone aldosterone, which is a mineralocorticoid receptor (MR) agonist, is associated with increased inflammation and risk of cardiovascular disease. MR antagonists are cardioprotective and antiinflammatory in vivo, and evidence suggests that they mediate these effects in part by aldosterone-independent mechanisms. Here we have shown that MR on myeloid cells is necessary for efficient classical macrophage activation by proinflarnmatory cytokines. Macrophages from mice lacking MR in myeloid cells (referred to herein as MyMRKO mice) exhibited a transcription profile of alternative activation. In vitro, MR deficiency synergized with inducers of alternatively activated macrophages (for example, IL-4 and agonists of PPAR gamma and the glucocorticoid receptor) to enhance alternative activation. In vivo, MR deficiency in macrophages mimicked the effects of MR antagonists and protected against cardiac hypertrophy, fibrosis, and vascular damage caused by L-NAME/Ang II. Increased blood pressure and heart rates and decreased circadian variation were observed during treatment of MyMRKO mice with L-NAME/Ang II. We conclude that myeloid MR is an important control point in macrophage polarization and that the function of MR on myeloid cells likely represents a conserved ancestral MR function that is integrated in a transcriptional network with PPAR gamma and glucocorticoid receptor. Furthermore, myeloid MR is critical for blood pressure control and for hypertrophic and fibrotic responses in the mouse heart and aorta.