Shi-Hao Ni1,2,3, Jin-Dong Xu4, Shu-Ning Sun1,2,3, Yue Li1,2,3, Zheng Zhou1,2,3, Huan Li1,2,3, Xin Liu1,2,3, Jian-Ping Deng1,2,3, Yu-Sheng Huang1,2,3, Zi-Xin Chen1,2,3, Wen-Jun Feng1, Jia-Jia Wang1,2,3, Shao-Xiang Xian1,2,3, Zhong-Qi Yang1,2,3, Sheng Wang4, Ling-Jun Wang1,2,3, Lu Lu1,2,3. 1. The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China. 2. Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China. 3. Key Laboratory of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China. 4. Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China.
Abstract
AIMS: The goal of our study was to investigate the heterogeneity of cardiac macrophages (CMφs) in mice with transverse aortic constriction (TAC) via single-cell sequencing and identify a subset of macrophages associated with heart injury. METHODS AND RESULTS: We selected all CMφs from CD45+ cells using single-cell mRNA sequencing data. Through dimension reduction, clustering, and enrichment analyses, CD72hi CMφs were identified as a subset of pro-inflammatory macrophages. The pseudo-time trajectory and ChIP-Seq analyses identified Rel as the key transcription factor that induces CD72hi CMφ differentiation. Rel KD and Rel-/- bone marrow chimaera mice subjected to TAC showed features of mitigated cardiac injury, including decreased levels of cytokines and ROS, which prohibited cardiomyocyte death. The transfer of adoptive Rel-overexpressing monocytes and CD72hi CMφ injection directly aggravated heart injury in the TAC model. The CD72hi macrophages also exerted pro-inflammatory and cardiac injury effects associated with myocardial infarction. In humans, patients with heart failure exhibit increased CD72hi CMφ levels following dilated cardiomyopathy and ischaemic cardiomyopathy. CONCLUSION: Bone marrow-derived, Rel-mediated CD72hi macrophages play a pro-inflammatory role, induce cardiac injury and, thus, may serve as a therapeutic target for multiple cardiovascular diseases. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The goal of our study was to investigate the heterogeneity of cardiac macrophages (CMφs) in mice with transverse aortic constriction (TAC) via single-cell sequencing and identify a subset of macrophages associated with heart injury. METHODS AND RESULTS: We selected all CMφs from CD45+ cells using single-cell mRNA sequencing data. Through dimension reduction, clustering, and enrichment analyses, CD72hi CMφs were identified as a subset of pro-inflammatory macrophages. The pseudo-time trajectory and ChIP-Seq analyses identified Rel as the key transcription factor that induces CD72hi CMφ differentiation. Rel KD and Rel-/- bone marrow chimaera mice subjected to TAC showed features of mitigated cardiac injury, including decreased levels of cytokines and ROS, which prohibited cardiomyocyte death. The transfer of adoptive Rel-overexpressing monocytes and CD72hi CMφ injection directly aggravated heart injury in the TAC model. The CD72hi macrophages also exerted pro-inflammatory and cardiac injury effects associated with myocardial infarction. In humans, patients with heart failure exhibit increased CD72hi CMφ levels following dilated cardiomyopathy and ischaemic cardiomyopathy. CONCLUSION: Bone marrow-derived, Rel-mediated CD72hi macrophages play a pro-inflammatory role, induce cardiac injury and, thus, may serve as a therapeutic target for multiple cardiovascular diseases. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Andrew L Koenig; Irina Shchukina; Junedh Amrute; Prabhakar S Andhey; Konstantin Zaitsev; Lulu Lai; Geetika Bajpai; Andrea Bredemeyer; Gabriella Smith; Cameran Jones; Emily Terrebonne; Stacey L Rentschler; Maxim N Artyomov; Kory J Lavine Journal: Nat Cardiovasc Res Date: 2022-03-16