Oppenheimer Atherosclerosis Research Center, Cedars Sinai Smidt Heart Institute, and Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.
Oppenheimer Atherosclerosis Research Center, Cedars Sinai Smidt Heart Institute, and Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.
J Am Coll Cardiol. 2018 Aug 21;72(8):885-904. doi: 10.1016/j.jacc.2018.05.061.
Macrophages are highly plastic cells that play an important role in the pathogenesis of cardiovascular disease.
This study 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 was 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 mice. This improvement was associated with the presence of a large number of proinflammatory Ly6C monocytes/macrophages and fewer reparative Ly6C 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.
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发挥重要作用。
本研究旨在探讨 GATA3 阳性巨噬细胞在心肌梗死（MI）后或在应对压力超负荷肥厚时调节心脏功能的作用。
生成髓系特异性 GATA3 缺陷（mGATA3KO）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。使用 GATA3 充足的 Cre 小鼠作为对照。进行免疫组织化学染色、流式细胞术、MILLIPLEX 小鼠细胞因子/趋化因子分析、培养巨噬细胞、定量实时聚合酶链反应和 Western blot 以确定 GATA3 在巨噬细胞中的作用。
GATA3 阳性巨噬细胞在急性 MI 后迅速积聚在心肌梗死区域。与对照组相比，GATA3 阳性巨噬细胞缺陷导致对急性 MI 或压力超负荷肥厚的心脏功能显著改善。这种改善与 mGATA3KO 小鼠心肌中存在大量促炎 Ly6C 单核细胞/巨噬细胞和较少的修复性 Ly6C 巨噬细胞有关。对 2 种小鼠基因型的血清蛋白进行分析，结果显示在 MI 前后，2 种小鼠基因型的血清生长因子和细胞因子图谱没有发生重大变化。研究发现，白细胞介素 4 通过近端启动子特异性和瞬时诱导培养巨噬细胞中的 GATA3，而远端启动子则保持沉默。此外，巨噬细胞中 GATA3 的缺失显著减弱了培养巨噬细胞中精氨酸酶-1 的表达。
我们证明了 GATA3 阳性巨噬细胞的存在会对缺血或压力超负荷引起的心肌重塑产生不利影响，而这些巨噬细胞的缺失则显著改善了心脏功能。靶向导致巨噬细胞中 GATA3 表达的信号通路可能会产生有利的心脏结局。
