A mighty small heart: the cardiac proteome of adult Drosophila melanogaster.

Development and Aging Program, NASCR Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
PLoS ONE (Impact Factor: 3.53). 04/2011; 6(4):e18497. DOI: 10.1371/journal.pone.0018497
Source: PubMed

ABSTRACT Drosophila melanogaster is emerging as a powerful model system for the study of cardiac disease. Establishing peptide and protein maps of the Drosophila heart is central to implementation of protein network studies that will allow us to assess the hallmarks of Drosophila heart pathogenesis and gauge the degree of conservation with human disease mechanisms on a systems level. Using a gel-LC-MS/MS approach, we identified 1228 protein clusters from 145 dissected adult fly hearts. Contractile, cytostructural and mitochondrial proteins were most abundant consistent with electron micrographs of the Drosophila cardiac tube. Functional/Ontological enrichment analysis further showed that proteins involved in glycolysis, Ca(2+)-binding, redox, and G-protein signaling, among other processes, are also over-represented. Comparison with a mouse heart proteome revealed conservation at the level of molecular function, biological processes and cellular components. The subsisting peptidome encompassed 5169 distinct heart-associated peptides, of which 1293 (25%) had not been identified in a recent Drosophila peptide compendium. PeptideClassifier analysis was further used to map peptides to specific gene-models. 1872 peptides provide valuable information about protein isoform groups whereas a further 3112 uniquely identify specific protein isoforms and may be used as a heart-associated peptide resource for quantitative proteomic approaches based on multiple-reaction monitoring. In summary, identification of excitation-contraction protein landmarks, orthologues of proteins associated with cardiovascular defects, and conservation of protein ontologies, provides testimony to the heart-like character of the Drosophila cardiac tube and to the utility of proteomics as a complement to the power of genetics in this growing model of human heart disease.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging is associated to disrupted contractility and rhythmicity, among other cardiovascular alterations. Drosophila melanogaster shows a pattern of aging similar to human beings and recapitulates the arrhythmogenic conditions found in the human heart. Moreover, the kinase CaMKII has been characterized as an important regulator of heart function and an arrhythmogenic molecule that participate in Ca2+ handling. Using a genetically engineered expressed Ca2+ indicator, we report changes in cardiac Ca2+ handling at two different ages. Aging prolonged relaxation, reduced spontaneous heart rate (HR) and increased the occurrence of arrhythmias, ectopic beats and asystoles. Alignment between Drosophila melanogaster and human CaMKII showed a high degree of conservation and indicates that relevant phosphorylation sites in humans are also present in the fruit fly. Inhibition of CaMKII by KN-93 (CaMKII-specific inhibitor), reduced HR without significant changes in other parameters. By contrast, overexpression of CaMKII increased HR and reduced arrhythmias. Moreover, it increased fluorescence amplitude, maximal rate of rise of fluorescence and reduced time to peak fluorescence. These results suggest that CaMKII in Drosophila melanogaster acts directly on heart function and that increasing CaMKII expression levels could be beneficial to improve contractility.
    PLoS ONE 07/2014; 9(7):e101871. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs are a class of endogenous small noncoding RNAs that regulate gene expression either by degrading target mRNAs or by suppressing protein translation. MicroRNAs have been found to be involved in many biological processes, such as development, differentiation and growth. However, the evolution of microRNA regulatory functions and networks has not been well studied. In this study, we conducted a cross-species analysis to study the evolution of cardiac microRNAs and their regulatory functions and networks. We found that conserved cardiac microRNA target genes have maintained highly conserved cardiac functions. Additionally, most of cardiac microRNA target genes in human with annotations of cardiac functions evolved from the corresponding homologous targets which are also involved in heart development related functions. Based on these results, we investigated the functional evolution of cardiac microRNAs and presented a functional evolutionary map. From this map, we identified the evolutionary time at which the cardiac microRNAs became involved in heart development or function and found that the biological processes of heart development evolved earlier than those of heart functions, e.g., heart contraction/relaxation or cardiac hypertrophy. Our study of the evolution of the cardiac microRNA regulatory networks revealed the emergence of new regulatory functional branches during evolution. Furthermore, we discovered that early evolved cardiac microRNA target genes tend to participate in the early stages of heart development. This study sheds light on the evolution of developmental features of genes regulated by cardiac microRNAs.
    Molecular Biology and Evolution 07/2014; · 14.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: For several decades, serum levels of alanine (ALT) and aspartate (AST) aminotransferases have been regarded as markers of liver injury, including a wide range of etiologies from viral hepatitis to fatty liver. The increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes, coronary heart disease, atherothrombotic risk profile, and overall risk of metabolic disease. Therefore, it is plausible to suggest that aminotransferases are surrogate biomarkers of "liver metabolic functioning" beyond the classical concept of liver cellular damage, as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function. In this study, we summarize the background information and recent findings on the biological role of ALT and AST, and review the knowledge gained from the application of genome-wide approaches and "omics" technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic functions. Prediction of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes, which suggest that regulation of aminotransferase activity is a complex and highly regulated trait. Finally, links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity.
    World journal of gastroenterology : WJG. 01/2015; 21(3):711-25.

Full-text (2 Sources)

Available from
May 28, 2014