Failing heart-specific cardiac fibroblasts induce heart failure via c-Myc

Heart failure (HF) is a global concern, marked by limited therapeutic options. While existing studies primarily focus on cardiomyocytes, there is a notable absence of drugs targeting noncardiomyocytes for HF. We focused on cardiac fibroblasts (CFs), utilising single-cell RNA-sequencing analysis. The analysis of murine hearts revealed one subcluster exclusive to the HF stage. The transcription factor c-Myc is specifically expressed in heart failure-specific fibroblasts (HF-Fibro). Cardiac fibroblast-specific deletion of c-Myc ameliorates pressure overload-induced cardiac dysfunction without affecting fibrosis. To elucidate the molecular function of c-Myc in HF-Fibro, transcriptome analysis by RNA-seq was conducted, in vivo. Overall design: Conditional deletion of c-Myc in CF were achieved by crossing c-Myc flox/flox homozygous mice with Tcf21 iCre hemizygous mice. c-Mycflox/flox;Tcf21 iCre (Myc-Tcf21-iCre) mice were used as c-Myc cardiac fibroblast-specific knockout (c-Myc KO) mice. Tamoxifen was administered intraperitoneally at a treatment dose of 45 mg/kg for 5 consecutive days to activate the inducible MerCreMer protein, thereby inducing Cre recombinase activity. Male mice (8–12 weeks old) underwent TAC surgery to induce cardiac hypertrophy, HF, or a sham operation. For RNA-seq sample preparation, total RNA was extracted from sham, TAC control, KO-TAC.