Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in heart failure with preserved ejection fraction.
Jan D LanzerLaura M WieneckeRicardo Omar Ramirez FloresMaura M ZyllaCelina KleyNiklas HartmannFlorian SicklingerJobst-Hendrik SchultzNorbert FreyJulio Saez-RodriguezFlorian LeuschnerPublished in: Basic research in cardiology (2024)
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.
Keyphrases
- single cell
- rna seq
- left ventricular
- high fat diet
- transcription factor
- wound healing
- heart failure
- oxidative stress
- ejection fraction
- genome wide
- nitric oxide synthase
- blood pressure
- adipose tissue
- high throughput
- rheumatoid arthritis
- nitric oxide
- newly diagnosed
- cell therapy
- magnetic resonance
- insulin resistance
- end stage renal disease
- poor prognosis
- stem cells
- metabolic syndrome
- mouse model
- cell proliferation
- mesenchymal stem cells
- type diabetes
- computed tomography
- chronic kidney disease
- cell death
- prognostic factors
- endothelial cells
- atrial fibrillation
- epithelial mesenchymal transition
- bone marrow
- emergency department
- magnetic resonance imaging
- single molecule
- amino acid
- endoplasmic reticulum stress
- high glucose
- long non coding rna
- dna binding
- cross sectional
- drug delivery
- transforming growth factor
- peripheral blood
- signaling pathway
- heat stress