Dataset Information

Hyperphosphorylation of sarcomeric proteins in heart failure with preserved ejection fraction: selective reversal of PKC hyperactivity by cell therapy

ABSTRACT: Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca2+-sensitivity and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model. Here, we quantified the phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart, Heart Left Ventricle

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Vidya Venkatraman

LAB HEAD: Dr. Jennifer Van Eyk

PROVIDER: PXD025555 | Pride | 2022-04-23

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	200208_SoetkampfD_S1.raw	Raw
	200208_SoetkampfD_S10.raw	Raw
	200208_SoetkampfD_S11.raw	Raw
	200208_SoetkampfD_S12.raw	Raw
	200208_SoetkampfD_S13.raw	Raw

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Publications

Myofilament Phosphorylation in Stem Cell Treated Diastolic Heart Failure.

Soetkamp Daniel D Gallet Romain R Parker Sarah J SJ Holewinski Ronald R Venkatraman Vidya V Peck Kiel K Goldhaber Joshua I JI Marbán Eduardo E Van Eyk Jennifer E JE

Circulation research 20211013 12

<h4>Rationale</h4>Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca<sup>2+</sup>-sensitivity, and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model.<h4>Objective</h4>Phosphorylation changes that und ...[more]

PMID: 34641704

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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.