| Autor: |
Chelko SP; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA.; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Penna VR; Department of Medicine, Washington University, St. Louis, Missouri, USA., Engel M; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA., Shiel EA; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA., Centner AM; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA., Farra W; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA., Cannon EN; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA., Landim-Vieira M; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA., Schaible N; Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA., Lavine K; Department of Medicine, Washington University, St. Louis, Missouri, USA., Saffitz JE; Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. |
| Abstrakt: |
Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) under basal conditions, and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single-cell RNA-Seq to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA-Seq and cellular indexing of transcriptomes and epitomes (CITE-Seq) studies revealed marked proinflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts, and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM. |
