Clonal Hematopoiesis–Driver DNMT3A Mutations Alter Immune Cells in Heart Failure

作者：Wesley Tyler Abplanalp, Sebastian Cremer, David John, Jedrzej Hoffmann, Bianca Schuhmacher, Maximillian Merten, Michael A. Rieger, Mariuca Vasa‐Nicotera, Andreas Michael Zeiher, Stefanie Dimmeler · 发表于：Circulation Research · 年份：2020 · DOI：10.1161/circresaha.120.317104 · 被引用次数：267 · 研究领域：Single-cell and spatial transcriptomics、Acute Myeloid Leukemia Research、Cardiac Fibrosis and Remodeling

Rationale: Clonal hematopoiesis driven by mutations of DNMT3A (DNA methyltransferase 3a) is associated with increased incidence of cardiovascular disease and poor prognosis of patients with chronic heart failure (HF) and aortic stenosis. Although experimental studies suggest that DNMT3A clonal hematopoiesis–driver mutations may enhance inflammation, specific signatures of inflammatory cells in humans are missing. Objective: To define subsets of immune cells mediating inflammation in humans using single-cell RNA sequencing. Methods and Results: Transcriptomic profiles of peripheral blood mononuclear cells were analyzed in n=6 patients with HF harboring DNMT3A clonal hematopoiesis–driver mutations and n=4 patients with HF and no DNMT3A mutations by single-cell RNA sequencing. Monocytes of patients with HF carrying DNMT3A mutations demonstrated a significantly increased expression of inflammatory genes compared with monocytes derived from patients with HF without DNMT3A mutations. Among the specific upregulated genes were the prototypic inflammatory IL (interleukin) IL1B (interleukin 1B), IL6, IL8 , the inflammasome NLRP3 , and the macrophage inflammatory proteins CCL3 and CCL4 as well as resistin, which augments monocyte-endothelial adhesion. Silencing of DNMT3A in monocytes induced a paracrine proinflammatory activation and increased adhesion to endothelial cells. Furthermore, the classical monocyte subset of DNMT3A mutation carriers showed increased expression of T-cell stimu...