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Cardiorenal heart failure with preserved ejection fraction is caused by a reversible rise of mineralocorticoid-induced fibroblast subtypes

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) is driven by co-morbidities. While specific treatments to enable recovery of HFpEF are lacking, recent clinical trials indicate beneficial effects of mineralocorticoid receptor (MR) antagonists. Here, we performed single nucleus RNA sequencing in an aldosterone/salt-induced model of cardiorenal HFpEF in mice and compared it to the high fat diet/L-NAME model of cardiometabolic HFpEF. We found a fibroblast subtype induced that is distinct from the classical myofibroblast observed in heart failure with reduced ejection fraction. Notably, after aldosterone withdrawal the HFpEF-like phenotype fully recovered. This was linked to a restored expression of MR target genes and an upregulation of collagen III, VI, and XV in fibroblasts during recovery. MR deletion from fibroblasts prevented cardiac remodeling and diastolic dysfunction, confirming the central role of fibroblast MR in cardiorenal HFpEF. In summary, our study reveals fibroblast gene expression signatures in heart failure from different causes that may determine the response to pharmacological treatment and potential for recovery.

ORGANISM(S): Mus musculus

PROVIDER: GSE312968 | GEO | 2025/12/09

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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Cardiorenal heart failure with preserved ejection fraction is caused by a reversible rise of mineralocorticoid-induced fibroblast subtypes

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