DNMT3A CHIP-driver mutations induce cardiac interstitial fibrosis through paracrine activation of fibroblasts via EGFR signaling, contributing to adverse outcomes in heart failure.
Do DNMT3A CHIP-driver mutations induce cardiac fibrosis in heart failure?
DNMT3A CHIP-driver mutations promote cardiac fibrosis via paracrine activation of fibroblasts by mutated monocytes, identifying a novel pathway for heart failure progression.
Abstract Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and the cardiac tissue. We demonstrate that CHIP augments macrophage-to-cardiac fibroblasts interactions. Mechanistically, the secretome of DNMT3A -silenced monocytes leads to myofibroblast activation, partially through epidermal growth factor (EGFR) signaling. Harboring DNMT3A CHIP-driver mutations is associated with increased cardiac interstitial fibrosis in mice and patients, and, thereby, may contribute to the poor outcome. These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies. Graphical abstract
Shumliakivska et al. (Mon,) conducted a other in Heart failure. DNMT3A CHIP-driver mutations vs. Without CHIP was evaluated on Cardiac interstitial fibrosis and myofibroblast activation. DNMT3A CHIP-driver mutations induce cardiac interstitial fibrosis through paracrine activation of fibroblasts via EGFR signaling, contributing to adverse outcomes in heart failure.