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Glycoproteins identified from heart failure and treatment models.

ABSTRACT: Conduction abnormalities can lead to dyssynchronous contraction, which significantly worsens morbidity and mortality of heart failure. Cardiac resynchronization therapy (CRT) can reverse ventricular remodeling and improve cardiac function. Although the underlying molecular changes are unknown, the use of a canine model of dyssynchronous heart failure (DHF) and CRT has shown that there are global changes across the cardiac proteome. This study determines changes in serum glycoprotein concentration from DHF and CRT compared to normal. We hypothesize that CRT invokes protective or advantageous pathways that can be reflected in the circulating proteome. Two prong discovery approaches were carried out on pooled normal, DHF, and CRT samples composed of individual canine serum to determine the overall protein concentration and the N-linked glycosites of circulating glycoproteins. The level of the glycoproteins was altered in DHF and CRT compared to control sera, with 63 glycopeptides substantially increased in DHF and/or CRT. Among the 32 elevated glycosite-containing peptides in DHF, 13 glycopeptides were reverted to normal level after CRT therapy. We further verify the changes of glycopeptides using label-free LC-MS from individual canine serum. Circulating glycoproteins such as alpha-fetoprotein, alpha-2-macroglobulin, galectin-3-binding protein, and collectin-10 show association to failing heart and CRT treatment model.

SUBMITTER: Yang S

PROVIDER: S-EPMC4492696 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Glycoproteins identified from heart failure and treatment models.

Yang Shuang S Chen Lijun L Sun Shisheng S Shah Punit P Yang Weiming W Zhang Bai B Zhang Zhen Z Chan Daniel W DW Kass David A DA van Eyk Jennifer E JE Zhang Hui H

Proteomics 20141009 2-3

Conduction abnormalities can lead to dyssynchronous contraction, which significantly worsens morbidity and mortality of heart failure. Cardiac resynchronization therapy (CRT) can reverse ventricular remodeling and improve cardiac function. Although the underlying molecular changes are unknown, the use of a canine model of dyssynchronous heart failure (DHF) and CRT has shown that there are global changes across the cardiac proteome. This study determines changes in serum glycoprotein concentratio ...[more]

PMID: 25141849

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Project description:BackgroundAccumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models.MethodsTwo independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet.ResultsThe KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P<0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2-treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values.ConclusionsChronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.

Project description:BackgroundHeart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets.MethodsWe investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis-protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis.ResultsForty-four of ninety proteins were positively associated with risk of incident HF (P<6.0×10-4). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1.ConclusionsWe identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.

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Glycoproteins identified from heart failure and treatment models.

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Glycoproteins identified from heart failure and treatment models.

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