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Expression data from healthy and diastolic heart failure rats

ABSTRACT: Heart failure (HF) with preserved ejection fraction (HFpEF) is rising, whose morbidity, mortality and healthcare costs are similar to HF with reduced ejection fraction (HFrEF). Although substantial molecular pathways lead to the changes in organ and tissue levels, there are still lack of successful treatments for HFpEF given the complexity molecular networks remaining unknown. Here we report that the significantly changed genes of HFpEF rats associates positively with inflammatory processes and immune responses while negatively with calcium ion transport into cytosol. GSEA analysis shows several KEGG pathways are significantly enriched in HFpEF rats including p53 signaling pathway, Toll like receptor signaling pathway and so on. Our study provides new insights into HFpEF pathogenesis and a new therapeutic against HFpEF.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE126062 | GEO | 2019/02/05

REPOSITORIES: GEO

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Project description:Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.

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Expression data from healthy and diastolic heart failure rats

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