Apabetalone prevented pulmonary hypertension development and rescued endothelial and fibroblast dysfunction in obese HFpEF mice by resetting lung microenvironmental alterations.
Does the BET protein inhibitor Apabetalone prevent pulmonary hypertension and modulate the lung microenvironment in a mouse model of obesity-induced HFpEF?
Apabetalone prevents pulmonary hypertension and resets the lung microenvironment in a mouse model of obesity-induced HFpEF, highlighting BET inhibitors as a potential therapeutic target.
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Abstract Background Obesity-related heart failure with preserved ejection fraction (obHFpEF) is the most common form of heart failure and is frequently complicated by the development of pulmonary hypertension (PH). The prevalence of PH in HFpEF ranges from 30% to 80%, and it is a strong predictor of mortality. Understanding changes of the lung microenvironment, namely cell-cell communications among fibroblasts, immune and endothelial cells, could unveil new targets to tackle microvascular dysfunction and PH in this setting. Epigenetic changes, namely post-translational histone modifications, are emerging as pivotal modulators of gene expression in cardiometabolic disease, and their therapeutic modulation by specific epi-drugs could rescue disease phenotypes. Purpose To investigate changes of the lung microenvironment in the obHFpEF lung and to test the effect of new epi-drugs on PH development. Methods Mice were fed a normal-diet (ND, control) or high-fat-diet (HFD) and L-NAME for 15 weeks to induce HFpEF. Control and obHFpEF mice were chronically treated with the BET protein inhibitor Apabetalone (APA) for 14 days. High resolution ultrasound imaging (Vevo 3100, Visualsonics) was employed to assess cardiac function and pulmonary pressure. Single-cell nuclei RNA sequencing (sc RNA-seq) was performed in lung specimens from the different experimental groups. Primary endothelial cells (mECs) and fibroblasts (mFs) were isolated from obHFpEF lungs and treated with APA for 48 hours. Results obHFpEF mice displayed PH, as evidenced by elevated pulmonary artery pressure, increased pulmonary artery resistance, extended right ventricular wall thickness, and diminished pulmonary artery acceleration time. In vivo treatment with APA prevented PH development in obHFpEF mice. To establish the cell types modulated by APA, we conducted scRNA-seq. The highest enrichment of genes whose expression was significantly correlated with echo-determined PH features was observed in mFs and mECs. Interactome analyses of our snRNAseq dataset showed that mFs are the primary source of intercellular signals in obHFpEF-PH lungs. Both mECs and mFs from HFpEF mice exhibited an altered phenotype. Specifically, mFs displayed a myo-fibroblast phenotype and an altered bioenergetic profile, as shown by Seahorse experiments, whereas mECs displayed defective autophagy and upregulation of NF-kB-related inflammatory genes, hypoxia-inducible factor (HIF1-α), and NADPH oxidase (NOX4). Of note, treatment with APA rescued mECs and mFs transcriptional alterations and cell dysfunction in obHFpEF mice. Conclusions APA can reset the lung microenvironment in a mouse model of obese HFpEF, thus reducing inflammation, cellular senescence and microvascular endothelial dysfunction. BET inhibitors may be promising epi-drugs to treat or prevent PH development in obese HFpEF
Telesca et al. (Sat,) reported a other. Apabetalone prevented pulmonary hypertension development and rescued endothelial and fibroblast dysfunction in obese HFpEF mice by resetting lung microenvironmental alterations.
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