Key result
DNMT3A CHIP mutations induce cardiac fibrosis via EGFR signaling, worsening heart failure outcomes.
Why the study?
DNMT3A driver mutations cause CHIP and portend adverse prognosis in HF, but interactions between CHIP-mutated cells and other cardiac cell types remain unknown.
Do DNMT3A CHIP-driver mutations induce cardiac fibrosis 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.
Answers are grounded in this paper and cite their sources.
Highlights potential DNMT3A-CHIP role in HF fibrosis; leaves open whether EGFR inhibition alters outcomes in patients.
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.
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Shumliakivska et al. (2023) studied 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.
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