Dataset Information

Proteomic and phosphoproteomic profiling in heart failure with preserved ejection fraction (HFpEF)

ABSTRACT: Although the prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, evidence-based therapies for HFpEF are rare, likely due to an incomplete understanding of this disease. This study sought to identify the cardiac-specific features of protein and phosphoprotein in a murine model of HFpEF using mass spectrometry. HFpEF mice developed moderate hypertension, left ventricle (LV) hypertrophy, lung congestion and diastolic dysfunction. Proteomics analysis of the LV tissue showed that 897 proteins were differentially expressed between HFpEF and Sham mice. We observed abundant changes in sarcomeric proteins, mitochondrial-related proteins, and NAD-dependent protein deacetylase sirtuin-3 (SIRT3). Upregulated pathways by GSEA analysis were related to immune modulation and muscle contraction, while downregulated pathways were predominantly related mitochondrial metabolism. Western blot analysis validated SIRT3 downregulated cardiac expression in HFpEF. Phosphoproteomics analysis showed that 72 phosphopeptides were differentially regulated between HFpEF and sham LV. Aberrant phosphorylation patterns mostly occurred in sarcomere proteins and nuclear-localized proteins associated with contractile dysfunction and cardiac hypertrophy. Seven aberrant phospho-sites were observed at the z disk binding region of titin. While total titin cardiac expression remained unaltered, its stiffer N2B isoform was significantly increased in HFpEF. Thus, these results show profound changes in proteins related to mitochondrial metabolism and function and the cardiac contractile apparatus in HFpEF. We propose that SIRT3 plays a key role and may be a target for drug development in HFpEF.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Heart Disease

SUBMITTER: Ryan Hekman

LAB HEAD: Flora Sam

PROVIDER: PXD033501 | Pride | 2022-10-15

REPOSITORIES: Pride

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			Action	DRS
	20190403_RH_MH_F10_Phos.raw	Raw
	20190403_RH_MH_F11_Phos.raw	Raw
	20190403_RH_MH_F12_Phos.raw	Raw
	20190403_RH_MH_F1_Phos.raw	Raw
	20190403_RH_MH_F2_Phos.raw	Raw

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Proteomic and phosphoproteomic profiling in heart failure with preserved ejection fraction (HFpEF).

Valero-Muñoz María M Saw Eng Leng EL Hekman Ryan M RM Blum Benjamin C BC Hourani Zaynab Z Granzier Henk H Emili Andrew A Sam Flora F

Frontiers in cardiovascular medicine 20220825

Although the prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, evidence-based therapies for HFpEF remain limited, likely due to an incomplete understanding of this disease. This study sought to identify the cardiac-specific features of protein and phosphoprotein changes in a murine model of HFpEF using mass spectrometry. HFpEF mice demonstrated moderate hypertension, left ventricle (LV) hypertrophy, lung congestion and diastolic dysfunction. Proteomics analysis ...[more]

PMID: 36093146

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