Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-Induced Cardiomyopathy Through the SR-A1-c-Myc Axis.
Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-Induced Cardiomyopathy Through the SR-A1-c-Myc Axis.
复制标题
心脏驻留修复巨噬细胞的自我维护通过 SR-A1-c-Myc 轴减轻阿霉素诱导的心肌病。
DOI：
10.1161/circresaha.119.316428
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发表时间：
2020
影响因子：
20.1
通讯作者：
Chen Qi
中科院分区：
文献类型：
--
作者：
Zhang Hanwen;Xu Andi;Sun Xuan;Yang Yaqing;Zhang Lai;Bai Hui;Ben Jingjing;Zhu Xudong;Li Xiaoyu;Yang Qing;Wang Zidun;Wu Wei;Yang Di;Zhang Yongjie;Xu Yong;Chen Qi
阿霉素诱导的心肌病（DiCM）是癌症患者心力衰竭和死亡的主要原因，其中巨噬细胞协调的炎症是重要的病理机制。然而，具体的作用，组织居民和单核细胞衍生的巨噬细胞在DiCM. Uncovering的起源，表型和功能的增殖心脏居民巨噬细胞和机械见解的自我维护的心脏巨噬细胞在DiCM progress.Methods和ResultsMice被给予阿霉素诱导心肌病。通过谱系追踪、联体共生和骨髓移植等方法观察宿主巨噬细胞和单核细胞源性巨噬细胞的动态变化。我们发现单核细胞源性巨噬细胞主要表现出促炎表型，其主导了整个DiCM病理过程并损害心脏功能。相比之下，心脏驻留巨噬细胞易受阿霉素损伤。存活的常驻巨噬细胞表现出增强的增殖，并赋予修复作用。SR-A1（A1类清道夫受体）的全局或骨髓特异性消融抑制心脏驻留修复巨噬细胞的增殖，因此，加剧了DiCM小鼠的心肌病。重要的是，骨髓移植证实了巨噬细胞SR-A1缺乏的有害影响。在机械水平上，我们表明，c-Myc（禽骨髓细胞瘤病毒癌基因细胞同源物），一个关键的转录因子的SR-A1-P38-SIRT 1（Sirtuin 1）通路，介导的效果SR-A1在修复性巨噬细胞增殖DiCM.ConclusionsThe SR-A1-c-Myc轴可能是一个有前途的目标，通过增强心脏驻留修复性巨噬细胞增殖治疗DiCM。
RationaleDoxorubicin-induced cardiomyopathy (DiCM) is a primary cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathological mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood.ObjectiveUncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression.Methods and ResultsMice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a proinflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of SR-A1 (class A1 scavenger receptor) inhibited proliferation of cardiac resident reparative macrophages and, therefore, exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of bone marrow. At the mechanistic level, we show that c-Myc (Avian myelocytomatosis virus oncogene cellular homolog), a key transcriptional factor for the SR-A1-P38-SIRT1 (Sirtuin 1) pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM.ConclusionsThe SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.