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: 3.23). 04/2011; 6(4):e18497. DOI: 10.1371/journal.pone.0018497
Source: PubMed


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.

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    • "Previous reports about similarities of CaMKII in Drosophila and mammals have referred to its presence and functionality in brain [37], [38]. More recently, a CaMKII isoform has been detected in Drosophila heart through mass spectrometry [39]. However, a possible role of CaMKII in Drosophila heart was not identified. "
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    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. DOI:10.1371/journal.pone.0101871 · 3.23 Impact Factor
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    • "Drosophila expresses two orthologs of human KIND2, Fermitin1 (Fit1) and Fermitin2 (Fit2) that contain a highly conserved FERM (4.1, Ezrin, Radixin, Moesin) domain which is required for binding to the cytoplasmic tail of β-integrins [18] (see Fig. 1B and Fig. S1). Both Fit1 and Fit2 message and protein are detected in adult heart tissue, consistent with a role in cardiac function [19], [20]. "
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    ABSTRACT: The vertebrate Kindlins are an evolutionarily conserved family of proteins critical for integrin signalling and cell adhesion. Kindlin-2 (KIND2) is associated with intercalated discs in mice, suggesting a role in cardiac syncytium development; however, deficiency of Kind2 leads to embryonic lethality. Morpholino knock-down of Kind2 in zebrafish has a pleiotropic effect on development that includes the heart. It therefore remains unclear whether cardiomyocyte Kind2 expression is required for cardiomyocyte junction formation and the development of normal cardiac function. To address this question, the expression of Fermitin 1 and Fermitin 2 (Fit1, Fit2), the two Drosophila orthologs of Kind2, was silenced in Drosophila cardiomyocytes. Heart development was assessed in adult flies by immunological methods and videomicroscopy. Silencing both Fit1 and Fit2 led to a severe cardiomyopathy characterised by the failure of cardiomyocytes to develop as a functional syncytium and loss of synchrony between cardiomyocytes. A null allele of Fit1 was generated but this had no impact on the heart. Similarly, the silencing of Fit2 failed to affect heart function. In contrast, the silencing of Fit2 in the cardiomyocytes of Fit1 null flies disrupted syncytium development, leading to severe cardiomyopathy. The data definitively demonstrate a role for Fermitins in the development of a functional cardiac syncytium in Drosophila. The findings also show that the Fermitins can functionally compensate for each other in order to control syncytium development. These findings support the concept that abnormalities in cardiomyocyte KIND2 expression or function may contribute to cardiomyopathies in humans.
    PLoS ONE 05/2013; 8(5):e62958. DOI:10.1371/journal.pone.0062958 · 3.23 Impact Factor
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    ABSTRACT: Congenital heart disease (CHD) represents a major cause for perinatal death and childhood morbidity. Understanding the molecular-genetic basis of CHD is therefore crucial for improved prenatal diagnosis and optimal therapeutic strategies. The power of Drosophila genetics has been utilized in recent years to identify new factors involved in human disease in general and CHD in particular. This review summarizes current approaches that aim to dissect models of CHD using classical genetics together with a multitude of newly developed methods for cardiac analysis in the fruit fly Drosophila.
    Drug Discovery Today Disease Models 06/2009; 6(2):47-54. DOI:10.1016/j.ddmod.2009.11.002
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