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Koser, F; Hobbach, AJ; Abdellatif, M; Herbst, V; Türk, C; Reinecke, H; Krüger, M; Sedej, S; Linke, WA.
Acetylation and phosphorylation changes to cardiac proteins in experimental HFpEF due to metabolic risk reveal targets for treatment.
Life Sci. 2022; 309:120998 Doi: 10.1016/j.lfs.2022.120998
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Co-Autor*innen der Med Uni Graz
Abdellatif Mahmoud
Sedej Simon
Trummer-Herbst Viktoria

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AIMS: Despite the high prevalence of heart failure with preserved ejection fraction (HFpEF), the pathomechanisms remain elusive and specific therapy is lacking. Disease-causing factors include metabolic risk, notably obesity. However, proteomic changes in HFpEF are poorly understood, hampering therapeutic strategies. We sought to elucidate how metabolic syndrome affects cardiac protein expression, phosphorylation and acetylation in the Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 (ZSF1) rat HFpEF model, and to evaluate changes regarding their potential for treatment. MAIN METHODS: ZSF1 obese and lean rats were fed a Purina diet up to the onset of HFpEF in the obese animals. We quantified the proteome, phosphoproteome and acetylome of ZSF1 obese versus lean heart tissues by mass spectrometry and singled out targets for site-specific evaluation. KEY FINDINGS: The acetylome of ZSF1 obese versus lean hearts was more severely altered (21 % of proteins changed) than the phosphoproteome (9 %) or proteome (3 %). Proteomic alterations, confirmed by immunoblotting, indicated low-grade systemic inflammation and endothelial remodeling in obese hearts, but low nitric oxide-dependent oxidative/nitrosative stress. Altered acetylation in ZSF1 obese hearts mainly affected pathways important for metabolism, energy production and mechanical function, including hypo-acetylation of mechanical proteins but hyper-acetylation of proteins regulating fatty acid metabolism. Hypo-acetylation and hypo-phosphorylation of elastic titin in ZSF1 obese hearts could explain myocardial stiffening. SIGNIFICANCE: Cardiometabolic syndrome alters posttranslational modifications, notably acetylation, in experimental HFpEF. Pathway changes implicate a HFpEF signature of low-grade inflammation, endothelial dysfunction, metabolic and mechanical impairment, and suggest titin stiffness and mitochondrial metabolism as promising therapeutic targets.
Find related publications in this database (using NLM MeSH Indexing)
Rats - administration & dosage
Animals - administration & dosage
Heart Failure - administration & dosage
Stroke Volume - physiology
Connectin - metabolism
Ventricular Function, Left - physiology
Phosphorylation - administration & dosage
Rats, Zucker - administration & dosage
Proteome - metabolism
Acetylation - administration & dosage
Proteomics - administration & dosage
Nitric Oxide - metabolism
Metabolic Syndrome - metabolism
Obesity - metabolism
Inflammation - metabolism
Protein Processing, Post-Translational - administration & dosage
Fatty Acids - administration & dosage

Find related publications in this database (Keywords)
Diastolic dysfunction
Meta -inflammation
Myocardial stiffness
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