Hanwen Zhang1,2, Andi Xu1,2, Xuan Sun1,3, Yaqing Yang1,2, Lai Zhang1,2, Hui Bai1,2, Jingjing Ben1,2, Xudong Zhu1,2, Xiaoyu Li1,2, Qing Yang1,2, Zidun Wang4, Wei Wu5, Di Yang4, Yongjie Zhang6, Yong Xu1,2, Qi Chen1,2. 1. From the Department of Pathophysiology (H.Z., A.X., X.S., Y.Y., L.Z., H.B., J.B., X.Z., X.L., Q.Y., Y.X., Q.C.), Nanjing Medical University, China. 2. Key Laboratory of Targeted Intervention of Cardiovascular Diseases, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Jiangsu Province, China (H.Z., A.X., Y.Y., L.Z., H.B., J.B., X.Z., X.L., Q.Y., Y.X., Q.C.). 3. Department of Cardiology, Nanjing Drum Tower Hospital, China (X.S.). 4. Department of Cardiology, First Affiliated Hospital with Nanjing Medical University, China (Z.W., D.Y.). 5. Bioinformatics (W.W.), Nanjing Medical University, China. 6. Anatomy (Y.Z.), Nanjing Medical University, China.
Abstract
RATIONALE: Doxorubicin-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. OBJECTIVE: Uncovering 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 RESULTS: Mice 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. CONCLUSIONS: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.
RATIONALE: Doxorubicin-induced cardiomyopathy (DiCM) is a primary cause of heart failure and mortality in cancerpatients, 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. OBJECTIVE: Uncovering 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 RESULTS:Mice 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. CONCLUSIONS: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.