Project description:Fibrosis is important pathogenesis in heart failure with preserved ejection fraction (HFpEF). We previously reported that the overexpression of cardiac transcription factors, Mef2c/Gata4/Tbx5/Hand2 (MGTH) could directly reprogram cardiac fibroblasts (CFs) into induced CMs (iCMs) and reduce fibrosis. Here we show that in vivo cardiac reprogramming generated iCMs from resident CFs, improved cardiac function, and reversed fibrosis in HFpEF model using a novel transgenic mouse system. RNA-seq revealed that the MGTH activated the cardiac program and concomitantly suppressed fibroblast and inflammatory signatures. Thus, cardiac reprogramming improves HFpEF via myocardial regeneration and anti-fibrosis.
Project description:Single cell sequencing in peripheral blood mononuclear cells (PBMCs) revealed a novel human-specific long noncoding RNA called heart-failure associated transcript 4 (HEAT4). HEAT4 expression was assessed in several in vitro and ex vivo models of immune cell activation, as well as in the blood of patients with heart failure (HF), acute myocardial infarction (AMI) and cardiogenic shock (CS). The transcriptional regulation of HEAT4 was verified through cytokine treatment and single cell sequencing. Loss-of-function and gain-of-function studies and multiple RNA–protein interaction assays uncovered a mechanistic role of HEAT4 in the monocyte anti-inflammatory gene program. HEAT4 expression and function was characterized in a vascular injury model in NOD.CB-17-Prkdc scid/Rj mice.
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
Project description:The goal of this dataset was to use RNA-seq in human heart tissue to delineate etiology-specific gene expression signatures in heart failure.
