Deficiency of GATA3-Positive Macrophages Improves Cardiac Function Following Myocardial Infarction or Pressure Overload Hypertrophy.
Deficiency of GATA3-Positive Macrophages Improves Cardiac Function Following Myocardial Infarction or Pressure Overload Hypertrophy.
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DOI：
10.1016/j.jacc.2018.05.061
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发表时间：
2018-08-21
影响因子：
24
通讯作者：
Shah PK
中科院分区：
文献类型：
--
作者：
Yang M;Song L;Wang L;Yukht A;Ruther H;Li F;Qin M;Ghiasi H;Sharifi BG;Shah PK
巨噬细胞是高度可塑性的细胞，在心血管疾病的发病机制中起重要作用。作者研究了GATA 3阳性巨噬细胞在心肌梗死（MI）后或对压力超负荷肥大的反应中调节心脏功能的作用。产生骨髓特异性GATA 3缺陷（mGATA 3 KO）小鼠;诱导MI或压力超负荷，并通过超声心动图测定心脏功能。GATA 3-充足的Cre小鼠用作对照。采用免疫组织化学染色、流式细胞术、MILLIPLEX小鼠细胞因子/趋化因子测定、培养的巨噬细胞、定量实时聚合酶链反应和western blot来确定GATA 3在巨噬细胞中的作用。GATA 3阳性巨噬细胞在急性MI后迅速聚集在心肌梗死区域。与对照组相比，GATA 3阳性巨噬细胞的缺乏导致急性MI或压力超负荷肥大时心脏功能的显著改善。与对照小鼠相比，这种改善与mGATA 3 KO小鼠心肌中大量促炎性Ly 6Chi单核细胞/巨噬细胞和较少的修复性Ly 6Clo巨噬细胞的存在相关。对2种小鼠基因型的血清蛋白分析显示，MI前后2种小鼠基因型之间的血清生长因子和细胞因子谱没有重大变化。GATA 3被发现是特异性和瞬时诱导白细胞介素4在培养的巨噬细胞通过活性的近端启动子，而远端启动子保持沉默。此外，巨噬细胞中GATA 3的缺乏显著减弱了培养的巨噬细胞中的GATA-1表达。我们证明，GATA 3阳性巨噬细胞的存在对心肌缺血或压力超负荷的心肌重塑产生不利影响，而这些巨噬细胞的缺乏导致心脏功能的显着改善。靶向导致巨噬细胞中GATA 3表达的信号通路可能具有有利的心脏结局。单核细胞/巨噬细胞在心脏疾病的发病机制中起关键作用。作者确定了一个巨噬细胞亚群，GATA 3阳性，在心肌梗死（MI）后积聚在心肌中。这种巨噬细胞亚群的基因耗竭显著改善了MI后或对压力超负荷的反应中的心脏功能。GATA 3阳性巨噬细胞的缺乏减少了缺血心肌中Ly 6Clo巨噬细胞的频率。这些数据表明，治疗靶向巨噬细胞中的GATA 3信号传导可能会改善心脏疾病的结局。
Macrophages are highly plastic cells that play an important role in the pathogenesis of cardiovascular disease. The authors investigated the role of GATA3-positive macrophages in modulating cardiac function after myocardial infarction (MI) or in response to pressure overload hypertrophy. Myeloid-specific GATA3-deficient (mGATA3KO) mice were generated; MI or pressure overload were induced, and cardiac function was determined by echocardiography. GATA3-sufficient Cre mice were used as a control. Immunohistochemical staining, flow cytometry, MILLIPLEX Mouse Cytokine/Chemokine Assay, cultured macrophages, quantitative real-time polymerase chain reaction, and western blot were used to determine the role of GATA3 in macrophages. GATA3-positive macrophages rapidly accumulated in the infarcted region of the myocardium after acute MI. Deficiency of GATA3-positive macrophages led to a significant improvement of cardiac function in response to acute MI or pressure overload hypertrophy compared with the control. This improvement was associated with the presence of a large number of proinflammatory Ly6Chi monocytes/macrophages and fewer reparative Ly6Clo macrophages in the myocardium of mGATA3KO mice compared with control mice. Analysis of serum proteins from the 2 mouse genotypes revealed no major changes in the profile of serum growth factors and cytokines between the 2 mice genotypes before and after MI. GATA3 was found to be specifically and transiently induced by interleukin 4 in cultured macrophages through activity of the proximal promoter, whereas the distal promoter remained silent. In addition, the absence of GATA3 in macrophages markedly attenuated arginase-1 expression in cultured macrophages. We demonstrated that the presence of GATA3-positive macrophages adversely affects remodeling of the myocardium in response to ischemia or pressure overload, whereas the absence of these macrophages led to a significant improvement in cardiac function. Targeting of signaling pathways that lead to the expression of GATA3 in macrophages may have favorable cardiac outcomes. Monocytes/macrophages play a critical role in the pathogenesis of cardiac diseases. The authors identified a subset of macrophages, GATA3-positive, that accumulate in the myocardium after myocardial infarction (MI). Genetic depletion of this macrophage subset significantly improved cardiac function after MI or in response to pressure overload. The absence of GATA3-positive macrophages reduced the frequency of Ly6Clo macrophages in the ischemic myocardium. The data suggest that therapeutic targeting of GATA3 signaling in macrophages may improve the outcome of cardiac diseases.
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DOI：
10.1161/circimaging.113.001093
发表时间：
2014-05-01
期刊：
Circulation. Cardiovascular imaging
影响因子：
--
作者：
Kim, Eung Ju;Kim, Sungeun;Seo, Hong Seog
通讯作者：
Seo, Hong Seog
影响因子：
4.4
作者：
Kurowska-Stolarska, Mariola;Stolarski, Bartosz;Liew, Foo Y.
通讯作者：
Liew, Foo Y.
冠状动脉发育和成熟需要原始的胚胎巨噬细胞。
影响因子：
20.1
作者：
Leid J;Carrelha J;Boukarabila H;Epelman S;Jacobsen SE;Lavine KJ
通讯作者：
Lavine KJ
影响因子：
3.7
作者：
Leblond AL;Klinkert K;Martin K;Turner EC;Kumar AH;Browne T;Caplice NM
通讯作者：
Caplice NM
DOI：
10.1016/j.bbadis.2012.09.014
发表时间：
2013-07
影响因子：
6.2
作者：
Borthwick, Lee A.;Wynn, Thomas A.;Fisher, Andrew J.
通讯作者：
Fisher, Andrew J.