Advertisement

Heart Failure Reviews

, Volume 22, Issue 1, pp 91–98 | Cite as

Molecular mechanisms of heart failure: insights from Drosophila

  • Shasha Zhu
  • Zhe Han
  • Yan Luo
  • Yulin Chen
  • Qun Zeng
  • Xiushan Wu
  • Wuzhou Yuan
Open Access
Article

Abstract

Heart failure places an enormous burden on health and economic systems worldwide. It is a complex disease that is profoundly influenced by both genetic and environmental factors. Neither the molecular mechanisms underlying heart failure nor effective prevention strategies are fully understood. Fortunately, relevant aspects of human heart failure can be experimentally studied in tractable model animals, including the fruit fly, Drosophila, allowing the in vivo application of powerful and sophisticated molecular genetic and physiological approaches. Heart failure in Drosophila, as in humans, can be classified into dilated cardiomyopathies and hypertrophic cardiomyopathies. Critically, many genes and cellular pathways directing heart development and function are evolutionarily conserved from Drosophila to humans. Studies of molecular mechanisms linking aging with heart failure have revealed that genes involved in aging-associated energy homeostasis and oxidative stress resistance influence cardiac dysfunction through perturbation of IGF and TOR pathways. Importantly, ion channel proteins, cytoskeletal proteins, and integrins implicated in aging of the mammalian heart have been shown to play significant roles in heart failure. A number of genes previously described having roles in development of the Drosophila heart, such as genes involved in Wnt signaling pathways, have recently been shown to play important roles in the adult fly heart. Moreover, the fly model presents opportunities for innovative studies that cannot currently be pursued in the mammalian heart because of technical limitations. In this review, we discuss progress in our understanding of genes, proteins, and molecular mechanisms that affect the Drosophila adult heart and heart failure.

Keywords

Drosophila Heart failure Molecular mechanisms Conserved 

Introduction

Heart failure (HF) is the culmination of diverse cardiac muscle pathophysiological insults resulting in a progressive and deleterious decline in heart function, such that the metabolic demands of the organism are not met. Clinically, this presents as dyspnea, fluid retention, and reduced tissue perfusion with death resulting from lethal arrhythmias or insufficient pump function [1]. The World Health Organization (WHO) has identified cardiovascular disease as the worldwide leading cause of death, and a profound economic healthcare burden. HF is the culmination of cardiovascular disease that can arise from diverse conditions including abnormal heart development or valve formation, coronary atherosclerosis, hypertension, acute pulmonary embolism, or emphysema. External influences, including pregnancy and fatigue, can also cause HF. Because cardiovascular diseases are complex, multifactorial pathologies associated with both genetic and environmental factors [2], the development of new pharmacological and device-based therapies for HF has proven disappointing.

HF is not unique to humans but is observed in many other species, and HF disease models have been developed in rats and mice and in larger mammals including dogs and pigs [3]. The Drosophila adult heart which is a linear tube comprising two rows of myocardial cells has recently been used to investigate aspects of cardiac biology relevant to understanding human HF. The Drosophila heart can be divided into thoracic and abdominal heart sections [4, 5]. The abdominal heart is divided by internal valves into four chambers which allow hemolymph to enter the heart after a contraction. Hemolymph provides nutrients and hormones to the fly’s internal organs, allowing flies to live for days with a severely damaged heart, because unlike mammals, there is a distinct non-cardiac system (tracheoles) that delivers oxygen to tissues. The myocardium surrounded by non-contractile pericardial cells contains spirally orientated myofibrils. It provides an excellent model with which to dissect out the cell-autonomous and non-autonomous mechanisms of heart failure.

In addition to its comparative simplicity, the Drosophila heart displays strikingly conserved structural and functional features which, combined with a much shorter lifespan and an unprecedented wealth of available experimental genetics tools, make it a powerful model system for the insights to explore molecular mechanisms underlying HF. Many genes, proteins, and molecular and cellular pathways involved in cardiac biology are well conserved from flies to humans [6]. These include, for example, highly conserved contractile proteins and ion channel proteins; contractile process-associated proteins. In addition,ion channels including CaMKII, dSUR, Ctrl, Ih/HCN [7] and KCNQ [8] are functionally conserved in fly and mammalian hearts. Furthermore, numerous genes regulating cardiac development are functionally conserved from flies to mammals [9], including Tinman/Nkx2.5, Neuromancer/TBX20, and Pannier/GATA4.

Together with the striking molecular and cellular conservation underlying heart development and function, advances in powerful methods allowing high resolution, accurate analysis of Drosophila heart biology such as Pacing, OCT (optical coherence tomography) [10], and atomic force microscopy (AFM) [11] also provide a compelling rationale for use of the fly model to elucidate fundamental mechanisms of HF. Insights thus obtained can be used to efficiently direct translational research into increasing costly, time-consuming, and technically challenging vertebrate models en route to clinical interventions.

Ion channel proteins contribute to heart failure

Ca2+ signaling is a classical pathway in maintenance of adult heart function. Wolf established a genetic method to monitor myocardial Ca2+ cycling in Drosophila, in which cardiac-specific expression of GCaMP2 acts as a genetically encoded calcium indicator. Ca2+ signaling in Drosophila myocardium is similar to that of the mammalian heart in several aspects [12]and may reveal promising pathways to address heart disease. Recent investigations show that Ca2+/calmodulin-dependent protein kinase and phosphatase play essential roles in the adult heart. For example, increased free cellular Ca2+ activates CaMKII, leading to phosphorylation of proteins involved in Ca2+ handling [13]. In Drosophila, cardiac-specific inhibition of CaMKII reduces heart rate and increases the incidence of asystole while overexpression of CaMKII increases spontaneous heart rate and reduces arrhythmias [14]. Because CaMKII function is conserved from flies to mammals, the modulation of Ca2+ handling via CaMKII targeting may address problems associated with cardiac aging in humans. Additional insights into potential approaches based on conserved pathways come from studies of calcineurin, a calcium/calmodulin-dependent protein phosphatase. Activated calcineurin is necessary and sufficient to drive cardiac hypertrophy [15]. Inhibition of galactokinase causes cardiomyopathy by suppressing activation of calcineurin, and galactokinase has been identified as a novel candidate modifier of calcineurin-induced cardiomyopathy in the fly [16].

Potassium K+ channels regulate heart rate and cardiac rhythm in both Drosophila and mammals [17]. In Drosophila, mutations in the KCNQ gene cause cardiac arrhythmias in the adult fly and thus KCNQ is protective and important for aging [8]. In addition, the ATP-sensitive K+ channel gene dSUR protects against heart failure due to stress responses. The expression of dSUR is diminished in the aged Drosophila heart, and inhibition of dSUR in young flies confers an aged heart phenotype. dSUR expression is regulated by Tinman and the GATA transcription factor Pannier, both of which are highly conserved cardiac regulatory factors [18].

This reference indicated that dietary copper restriction in rats results in cardiomyopathy and decreases in cytochrome c oxidase as well as decreases in levels of the delta-subunit of ATP synthase [19]. Cu deficiency leads to severe cardiovascular dysfunction including cardiac hypertrophy [20]. Cardiac-specific knockout of Ctr1(copper transporter receptor) leads to cardiac hypertrophy in both Drosophila and mouse [21].

Energy homeostasis and heart function

Metabolism of sugars and fats are conserved between mammals and flies, and Drosophila heart function is affected by high-sugar diet (HSD) and high-fat diet (HFD), as well as time-restricted feeding (TRF) [22]. These results suggest that heart function is closely related to energy homeostasis in Drosophila.

Insulin/insulin-like growth factor (IGF) signaling is a well-established genetic pathway regulating longevity [23, 24]. Drosophila mutants of insulin-like receptor (InR) and chico (encoding the insulin receptor substrate) extend the lifespan of the organism as well as protect the heart from decreased resting heart rate and increased heart failure. Additionally, interfering with InR signaling exclusively in the heart, by overexpression of the phosphatase dPTEN or the forkhead transcription factor dFOXO (negative regulators of insulin/IGF signaling), prevents age-related decline in cardiac fitness. Moreover, the ablation of insulin-producing cells (IPCs) in flies also slows demographic aging and reduces age-dependent heart failure, indicating that both a reduction of insulin receptor signaling and circulating insulin levels influence organismal aging and age-related cardiac susceptibility to pacing stress [24, 25].

Another example showing how alterations in energy homeostasis can be coupled to aging and organ senescence is illustrated by manipulations of the Drosophila target of rapamycin (dTOR) pathway. A recent study showed that lowering TOR activity in Drosophila prevented age-dependent functional decline of heart performance. The evidence indicates that the Eif4e-binding protein (d4eBP) acts tissue autonomously and downstream of dTOR and dFOXO in the myocardium, where it enhances cardiac stress resistance and maintains normal heart rate and myogenic rhythm. Moreover, d4eBP is sufficient to protect long-term cardiac function against age-related decline and that up-regulation of dEif4e is sufficient to recapitulate the effects of high dTOR or insulin signaling [26].

EGFR pathway mediated heart failure

RTK (receptor tyrosine kinase) signaling, including EGFR, is essential for maintaining heart function in humans. RTK inhibition provokes dilated cardiomyopathies in mammalian heart models [27]. Recent studies in flies and mammals show that both activation and inhibition of EGFR signaling pathways result in heart failure but involve different mechanisms.

In mammals, ERK regulation of balanced concentric and eccentric cardiac growth is an established model [28]. Concentric hypertrophy, also called diastolic heart failure, is associated with thickening of the heart wall without dilation of the left ventricle. Eccentric hypertrophy, also called systolic heart failure or dilated cardiomyopathy, involves heart chamber enlargement with thinning of walls and poor myocardium contractility. In Drosophila, cardiac chamber enlargement is caused by inhibition of rhomboid 3 and the Spitz–EGFR pathway and by inhibition of either the EGF ligand or EGFR [29]. Cardiac-specific activation of EGFR, Ras, or Raf in Drosophila causes cardiac hypertrophy with decreased heart chamber lumen and enlarged cardio myocytes, but without changes of cardiomyocyte cell numbers. In Drosophila, enlarged cardiac chambers may result from addition of sarcomeres. Enlarged myocytes may be associated with the addition of parallel sarcomeres or increased myofibers [30]. EGF signaling, then, is evolutionarily conserved from flies to mammals and its accuracy is required for maintenance of adult heart function.

Heart failure associated with stress resistance

Oxidative stress contributes to the pathogenesis of age-related heart failure in the fly, associated with decreased stress resistance [9].

The degeneration driven by oxidation is counterbalanced by several pathways involved in repair of oxidative damage and redox balance. The Nrf2 (nuclear factor E2-related factor 2) pathway is important in this regard. In the mouse, the Nrf2 pathway is associated with repair of damage from inflammatory and autoimmune conditions, neurodegeneration, cancer, and other causes [31]. The Nrf2 pathway is an evolutionarily conserved regulator of longevity from invertebrates to mammals. The activation of Nrf2 signaling extends lifespan in many animal models including Drosophila and Caenorhabditis elegans [32]. However, the molecular mechanisms of its anti-aging function are not clear.

MafS (Drosophila small Maf protein), a dimerization partner of Nrf2, is the key component in the Nrf2 stress response. With increasing age, the ability to activate Nrf2 targets for stress resistance progressively declines in Drosophila. In aged flies, MafS overexpression protects the heart by preserving the accuracy of Nrf2 signaling [33]. Nrf2 anti-aging function declines in other animals as well, including Macaca mulatta [34].

Many studies have addressed the regulatory mechanism involved in oxidative stress. Classically, research into the effects of reactive oxygen species (ROS) focused on cell-autonomous signaling [35]. ROS also act as paracrine signaling mediators of the injury response by diffusing into nearby cells. Paracrine interactions between myocytes and non-myocytes are known to be important for normal myocardium development and function but underlying mechanisms are not well defined [36]. Recent studies suggest that ROS can mediate paracrine interactions in the fly heart under physiological conditions, with ROS generated by pericardial cells regulating myocardial function [37]. Surprisingly, this occurs not through direct intercellular signaling by ROS but indirectly through D-MKK3-D-p38 signaling in pericardial cells by ROS-induced activation, which influences myocardial function via cell–cell communication [36]. Anti-oxidant treatment studies to address aging in mammals have very mixed results. It is therefore not yet clear if this represents a viable treatment strategy to combat heart failure.

Canonical Wnt signaling and heart failure

The Wnt signaling pathway is an evolutionarily conserved signaling cascade that plays essential roles in embryonic development including heart development [38]. Wnt signaling is also important in adult, stem cell regulation, skeletal muscle regeneration, and cancer progression [39, 40], and recent studies indicated that Wnt signaling may be a novel target for treatment of heart failure. In mice, Wnt/β-catenin signaling contributes to heart failure, characterized by skeletal muscle myopathy, through direct interaction with FOXO. Also, activation of Wnt signaling contributes to fiber type shift toward fatigable fiber in chronic heart failure [41]. In a murine model of myocardial infarction, increased canonical Wnt signaling ameliorates fibrosis and cardiac dysfunction through elevated heme oxygenase-1, adiponectin, and increased angiogenesis [42]. Furthermore, Dickkopf-3 (DKK3), a modulator of Wnt signaling, promotes cardiac protection by interrupting the ASK1-JNK/p38 signaling cascade in mice [43]. Taken together, these results show that novel therapeutic targets for curing heart failure might be found in the Wnt signaling pathway. In Drosophila, a body of evidence suggests that Wnt signaling may be less important for adult heart function.

In the fly, pygo is essential for maintaining the structure and function of the adult heart but functions independently of Wnt signaling [44, 45]. Cardiac-specific knockdown of pygo drastically compromised heart function and structure, but, knockdown of other canonical Wnt signaling components, such as arm/β-Cat or pan/TCF, caused only mild cardiac defects. Also, pygo mutants fail to show significant genetic interaction with Wnt signaling components. Pygo was also shown to be independent of Wnt signaling in lens development [46] and human cancer [47]. Pygo may be associated with histone modification. It was reported that pygo could interact with Lgs to form a Pygo-BCL9/Lgs-H3K4me complex to regulate Wnt targets [48, 49], and Pygo also combined with the WDR5 core component of H3K4 histone methyl transferase (HMT) [50], suggesting pygo involvement in epigenetic modifications that regulate cardiac function.

Cytoskeletal remodeling and heart failure

The cortical cytoskeleton in cardiomyocytes which couples sarcomere to the membrane at cell–matrix and cell–cell junctions and translates sarcomeric contraction into cell shortening undergoes remodeling in aging and during heart failure [51]. The sarcomere is the fundamental unit of muscle, consisting mainly of cytoskeletal proteins. In addition, sarcomeric myosin heavy chain (Mhc), troponin T, sarcoglycan, dystrophin, and integrin are critical for normal muscle function. The cytoskeleton is subject to turnover throughout the lifespan in Drosophila. Screening for cytoskeletal and associated proteins in Drosophila revealed 46 genes needed for muscle function, many not previously reported [52].

Integrins are transmembrane receptors that mediate adhesion between the cell and its external environment (such as the extracellular matrix, ECM). Activation of integrins has an effect on cytoskeletal remodeling [53]. There are also reports that integrin-linked kinase( Ilk) promotes senescence of cardiac cells in the rat. Overexpressing Ilk specifically in cardiac fibroblasts caused cell senescence, while inhibiting Ilk ameliorated senescence-related phenomena [54]. However, other studies came to the opposite conclusion, with Ilk playing a protective role and inhibited Ilk inducing serious cardiac defects sufficient to cause a sudden death [55]. In Drosophila, Ilk/integrin was shown to play dual roles in modulating cardiac aging [56], such that overexpression or severe inhibition of Ilk/integrin signaling in young flies caused an accelerated cardiac-aging phenotype, while moderate reduction ameliorated the phenotype. Thus, results from the fly model can confirm the observations from mammalian studies and together show Ilk/integrin signaling important for normal longevity and heart function.

Integrin signaling was reportedly regulated by conserved vertebrate proteins called kindlins [57]. Kindlin-2 was suggested to play a role in the development of cardiac syncytium [58] and this was confirmed in Drosophila. There are two orthologues of vertebrate kindlin-2 in Drosophila, Fermitin1 and Fermitin2, and silencing both them can cause heart failure due to the inability of cardiomyocytes to form a functional syncytium [59]. Kindlin-2 is structurally and functionally conserved from invertebrates to vertebrates, essential for maintenance of heart function through regulation of integrin signaling.

The integrin-like protein vinculin is reportedly associated with heart failure in humans, and carriers of vinculin missense mutation are more sensitive to HF [60]. In Drosophila, cardiac-specific vinculin overexpression was associated with increased myocardial shortening velocity, 150% longer median life span, and partial rescue of cardiac deficiency due to cardiac myosin heavy chain knockdown. These observations suggest that vinculin reinforces the myocardial cytoskeleton and positively influences contractility and prolongs life. Kaushik et al. also showed that age-related increase in vinculin is conserved across humans, rhesus monkeys, rats, mice, and Drosophila [61].

Statin mechanisms in the Drosophila heart

Statins, such as simvastatin, are a mainstay of cardiovascular disease therapy. Molecular mechanisms are well described, including protein prenylation [62]. In Drosophila, simvastatin can protect adult cardiac function, significantly prolong life, reduce arrhythmia, and increase contractility. These functions appear to be associated with down-regulation of protein prenylation, rather than changes in juvenile hormone or ubiquin levels [63]. Moreover, isoprenoid synthesis inhibitors increased Drosophila lifespan. In mice, simvastatin down-regulated Ras GTPase prenylation leading to weaker membrane association. Overall, these results provide direct evidence that statins protect cardiac function and prolong life span by reducing protein prenylation.

CCR4-Not complex and chromatin remodeling

The CCR4-Not complex is evolutionarily highly conserved, with roles in chromatin transcriptional activation, RNA deadenylation, and microRNA-mediated mRNA degradation [64, 65, 66]. A frequently occurring Not3 SNP is correlated with abnormal cardiac QT intervals, which cause arrhythmias. In Drosophila, recent studies confirm that RNAi-mediated silencing of the CCR4-Not components Not3 and UBC4 in adult flies induced myofibrillar disarray and dilated cardiomyopathy [67]. In mice, not3 +/− heterozygotes exhibit spontaneous cardiac contractility defects and greater susceptibility to heart failure [68]. A link to epigenetic chromatin remodeling was suggested by reversal of these defects through inhibition of HDACs.

Scox/Sco and apoptosis in cardiomyopathy

In humans, Sco1 and Sco2 gene mutations resulting in cytochrome C oxidase (COX) deficiency are associated with cardiomyopathy [69]. Drosophila has a single orthologue of Sco1 and Sco2, called Scox. Heart-specific knockdown of Scox induced dilated cardiomyopathy and reduced adult fly lifespan. It was shown that p53-dependent apoptosis was directly implicated in development of the fly cardiomyopathy. In Sco2 knockout mice apoptosis is increased in the muscle and liver, strongly implicating cell death in COX deficiency-associated cardiomyopathy caused by Sco gene mutations in humans [70].

Neurodegenerative disease and heart function

Epidemiological evidence reveals an association between HF and neurodegenerative disease. The mechanisms by which certain genes may underlie this linkage have been studied in Drosophila. Presenilin gene mutations lead to early-onset familial Alzheimer’s disease and can cause dilated cardiomyopathy. In flies, either knockdown or overexpression of the Drosophila orthologue of mammalian Presenilin (dPsn) increased age-related cardiac arrhythmias and both myofibrillar and mitochondrial degeneration [71]. Altering dPsn also affected key calcium signaling genes such as inositol 1, 4, 5-triphosphate receptor (dIP3R), dSERCA, and RyR gene [24].

Huntington’s disease (HD), caused by expanded Huntingtin protein’s polyglutamine (PolyQ) repeats, is associated with both cardiovascular events including heart failure and amyloid-like inclusions, and heart failure causes high mortality among HD patients [72, 73]. Research in the Drosophila heart model provides insights into molecular mechanisms of HF induced by amyloid protein. Both ROS stress response pathways and amyloid protein unfolding can mediate the detrimental effects of PolyQ in the Drosophila heart [74].

One of the main pathologic processes associated with Parkinson’s disease and cardiomyopathy is functional disorder of PTEN-inducible kinase 1 (PINK1), Parkin, which mediates mitophagic elimination of damaged or senescent mitochondria [75]. In Drosophila, knockout of Parkin and cardiac-specific Parkin suppression both caused cardiomyopathy and mitochondrial abnormalities. This was completely prevented by suppressing cardiomyocyte mitochondrial fusion suggesting a central role of mitochondrial fusion in the cardiomyopathy caused by impaired mitophagy [76].

Conclusion

Despite clear anatomical differences between the invertebrate and vertebrate hearts, many key processes and regulatory mechanisms driving cardiac development and function are evolutionarily conserved from Drosophila to humans. Thus, the fly heart can be used to model HF mechanisms.

Abnormal ion channels contribute to heart failure, and inhibition of CaMKII reduced spontaneous heart rate and increased the incidence of asystole. Copper (Cu) is required in cardiac tissue mitochondrial oxidative phosphorylation to provide energy for cardiac contraction. K+ channels are conserved in regulating heart rate and rhythm in both Drosophila and mammals. The strong conservation of energy metabolism including IGF and dTOR signaling extends to the regulation of obesity, as well as effects on adult cardiac function. Furthermore, the interactions between IGF and dTOR signaling were discovered in Drosophila. Cardiac ROS, increased by a high-calorie diet, also plays an important role in HF. Drosophila studies have revealed distinctions in Wnt signaling pathway contributions to adult heart function, suggesting the emergence of epigenetic mechanisms of target gene activation. Statins prolong lifespan and protect adult cardiac function by reducing protein prenylation. The study of heart failure may also contribute to understanding of molecular mechanisms of neurodegenerative diseases.

From the standpoint of advancing therapeutic interventions to treat HF, Drosophila is the model platform par excellence for the design and conduct of whole animal, in vivo screening approaches to identify small molecules targeting key genes, proteins, and pathways in the development of heart disease.

Notes

Acknowledgements

This study was supported in part by grants from the National Natural Science Foundation of China(Nos. 81170229, 81370451, 81470449, 81670290), and the Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province (No. 2013-448-6).

References

  1. 1.
    Houser SR, Margulies KB, Murphy AM et al (2012) Animal models of heart failure: a scientific statement from the American Heart Association [J]. Circ Res 111(1):131–150CrossRefPubMedGoogle Scholar
  2. 2.
    Kypreos KE, Zafirovic S, Petropoulou PI et al (2014) Regulation of endothelial nitric oxide synthase and high-density lipoprotein quality by estradiol in cardiovascular pathology [J]. J Cardiovasc Pharmacol Ther 19(3):256–268CrossRefPubMedGoogle Scholar
  3. 3.
    Patten RD, Hall-Porter MR (2009) Animal models of heart failure: a scientific statement from the American Heart Association [J].Circ. Heart Fail 2(2):138–144CrossRefGoogle Scholar
  4. 4.
    Lehmacher C, Abeln B, Paululat A (2012) The ultrastructure of Drosophila heart cells [J]. Arthropod structure & development 41:459–474CrossRefGoogle Scholar
  5. 5.
    Rizki TM (1978) The circulatory system and associated cells and tissues. In: Ashburner M, Wright TR (eds) The genetics and biology of drosophila[M]. Academic Press, New York, NYGoogle Scholar
  6. 6.
    Nishimura M, Ocorr K, Bodmer R, Cartry J (2011) Drosophila as a model to study cardiac aging[J].Exp. Gerontol 46(5):326–330Google Scholar
  7. 7.
    Gonzalo-Gomez A, Turiegano E, León Y et al (2012) Ih current is necessary to maintain normal dopamine fluctuations and sleep consolidation in Drosophila [J]. PLoS One 7(5):e36477CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ocorr K, Reeves NL, Wessells RJ et al (2007) KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging [J]. Proc Natl Acad Sci U S A 104:3943–3948CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ocorr K, Perrin L, Lim HY, Qian L, Wu XS, Bodmer R (2007) Genetic control of heart function and aging in Drosophila [J].Trends. Cardiovasc Med 17(5):177–182Google Scholar
  10. 10.
    Wolf MJ, Amrein H, Izatt JA, Choma MA, Reedy MC, Rockman HA (2006) Drosophila as a model for the identification of genes causing adult human heart disease [J].Proc. Natl Acad Sci U S A 103(5):1394–1399CrossRefGoogle Scholar
  11. 11.
    Kaushik G, Zambon AC, Fuhrmann A, Bernstein SI et al (2012) Measuring passive myocardial stiffness in Drosophila melanogaster to investigate diastolic dysfunction [J]. J Cell Mol Med 16:1656–1662CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lin N, Badie N, Yu L, Abraham D, Cheng H, Bursac N, Rockman HA, Wolf MJ (2011) A method to measure myocardial calcium handling in adult Drosophila [J]. Circ Res 108(11):1306–1315CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hudmon A, Schulman H (2002) Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II [J]. Biochem J 364(Pt 3):593–611CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Santalla M, Valverde CA, Harnichar E, Lacunza E, Aguilar-Fuentes J, Mattiazzi A, Ferrero P1 (2014) Aging and CaMKII alter intracellular Ca2+ transients and heart rhythm in Drosophila melanogaster[J]. PLoS One 9(97):e101871CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wilkins BJ, Molkentin JD (2002) Calcineurin and cardiac hypertrophy: where have we been? Where are we going? [J]. JPhysiol 541:1–8CrossRefGoogle Scholar
  16. 16.
    Lee TE, Yu L, Wolf MJ, Rockman HA (2014) Galactokinase is a novel modifier of calcineurin- induced cardiomyopathy in Drosophila [J]. Genetics 198(2):591–603CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gu GG, Singh S (1995) Pharmacological analysis of heartbeat in Drosophila [J]. J Neurobiol 28:269–280CrossRefPubMedGoogle Scholar
  18. 18.
    Akasaka T, Klinedinst S, Ocorr K, Bustamante EL, Kim SK, Bodmer R (2006) The ATP–sensitive potassium (KATP) channel–encoded dSUR gene is required for Drosophila heart function and is regulated by tinman [J]. Proc Natl Acad Sci U S A 103(32):1999–2004CrossRefGoogle Scholar
  19. 19.
    Medeiros DM, Davidson J, Jenkins JE (1993) A unified perspective on copper deficiency and cardiomyopathy [J]. Proc Soc Exp Biol Med 203:262–273CrossRefPubMedGoogle Scholar
  20. 20.
    Mandinov L, Mandinova A, Kyurkchiev S, Kyurkchiev D et al (2003) Copper chelation represses the vascular response to injury [J]. Proc Natl Acad Sci U S A 100:6700–6705CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim BE, Turski ML, Nose Y, Casad M, Rockman HA, Thiele DJ (2010) Cardiac copper deficiency activates a systemic signaling[J]. Cell Metab 11(5):353–363CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Diop SB, Bodmer R (2015) Gaining insights into diabetic cardiomyopathy from Drosophila[J]. Trends in Endocrinology & Metabolism 26(11):618–627CrossRefGoogle Scholar
  23. 23.
    Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E et al (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein [J]. Science 5514:104–106CrossRefGoogle Scholar
  24. 24.
    Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function [J]. Science 5514:107–110CrossRefGoogle Scholar
  25. 25.
    Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, Bodmer R (2004) Insulin regulation of heart function in aging fruit flies [J]. Nat Genet 12:1275–1281CrossRefGoogle Scholar
  26. 26.
    Wessells R, Fitzgerald E, Piazza N, Ocorr K et al (2009) D4eBP acts downstream of both dTOR and dFOXO to modulate cardiac functional aging in Drosophila [J]. Aging Cell 8:542–552CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Chen MH, Kerkelä R, Force T (2008) Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics[J]. Circulation 118:84–95CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kehat I, Davis J, Tiburcy M, Accornero F et al (2011) Extracellular signal-regulated kinases 1 and 2 regulate the balance between eccentric and concentric cardiac growth[J]. Circ Res 108:176–183CrossRefPubMedGoogle Scholar
  29. 29.
    Yu L, Lee T, Lin N, Wolf MJ (2010) Affecting rhomboid-3 function causes a dilated heart in adult Drosophila[J]. PLoS Genet 6:e1000969CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yu L, Daniels J, Glaser AE, Wolf MJ (2013) Raf-mediated cardiac hypertrophy in adult Drosophila [J]. Disease Models & Mechanisms (6):964–976Google Scholar
  31. 31.
    Yu X, Kensler T (2005) Nrf2 as a target for cancer chemoprevention. Mutat Res 591:93–102CrossRefPubMedGoogle Scholar
  32. 32.
    Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans health span via AMPK, LKB1, and SKN-1. PLoS One 5:e8758CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rahman MM, Sykiotis GP, Nishimura M, Bodmer R, Bohmann D (2013) Declining signal dependence of Nrf2-MafS-regulated gene expression correlates with aging phenotypes[J]. Aging Cell 12(4):554–562CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D et al (2011) Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta[J]. J Gerontol A Biol Sci Med Sci 66:866–875CrossRefPubMedGoogle Scholar
  35. 35.
    Thannickal VJ, Fanburg BL (2000) Reactive oxygen species in cell signaling[J]. Am J Physiol Lung Cell Mol Physiol 279:L1005–L1028PubMedGoogle Scholar
  36. 36.
    Lim HY, Wang W, Chen J, Ocorr K, Bodmer R (2014) ROS regulate cardiac function via a distinct paracrine mechanism[J]. Cell Rep 7:35–44CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Owusu-Ansah E, Banerjee U (2009) Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation[J]. Nature 461:537–541CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wu X (2010) Regulation of Wg/Wnt signaling pathways in heart development [M]. Shaping the Heart in Development and Disease 4:41–79Google Scholar
  39. 39.
    Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis[J]. Science 317:807–810CrossRefPubMedGoogle Scholar
  40. 40.
    Anastas JN, Moon RT (2013) Wnt signalling pathways as therapeutic targets in cancer[J]. Nat Rev Cancer 13:11–26CrossRefPubMedGoogle Scholar
  41. 41.
    Okada K, Naito AT, Higo T, Nakagawa A, Shibamoto M et al (2015) Wnt/β-catenin signaling contributes to skeletal myopathy in heart[J]. Circ Heart Fail 8(4):799–808CrossRefPubMedGoogle Scholar
  42. 42.
    Cao J, Tsenovoy PL, Thompson EA, Falck JR, Touchon R, Sodhi K, Rezzani R, Shapiro J, Abraham NG (2015) Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway [J]. Prostaglandins Other Lipid Mediat 116-117:76–86CrossRefPubMedGoogle Scholar
  43. 43.
    Bao MW, Cai Z, Zhang XJ, Li L et al (2015) Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction [J]. Basic Res Cardiol 110(3):25CrossRefPubMedGoogle Scholar
  44. 44.
    Tang M, Yuan WZ, Bodmer R, Ocorr K, Wu XS (2014) The role of pygopus in the differentiation of intracardiac valves in Drosophila [J]. Genesis 52(1):19–28CrossRefPubMedGoogle Scholar
  45. 45.
    Tang M, Yuan WZ, Fan XW, Liu M, Bodmer R, Ocorr K, Wu XS (2013) pygopus maintains heart function in aging Drosophila independently of canonical Wnt signaling [J]. Circ Cardiovasc Genet 6(5):472–480CrossRefPubMedGoogle Scholar
  46. 46.
    Cantù C, Zimmerli D, Hausmann G et al (2014) Pax6-dependent, but b-catenin-independent, function of Bcl9 proteins in mouse lens development [J]. Genes Dev 28:1879–1884CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Popadiuk CM, Xiong J, Wells MG et al (2006) Antisense suppression of pygopus2 results in growth arrest of epithelial ovarian cancer [J]. Clin Cancer Res 12(7 Pt 1):2216–2223CrossRefPubMedGoogle Scholar
  48. 48.
    Fiedler M, Sanchez-Barrena MJ, Nekrasov M et al (2008) Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex[J]. Cell Molecular 30(4):507–518CrossRefGoogle Scholar
  49. 49.
    De La Roche M, Bienz M (2007) Wingless-independent association of pygopus with dTCF target genes [J]. Curr Biol 17(6):556–561CrossRefPubMedGoogle Scholar
  50. 50.
    Gu B, Sun P, Yuan Y et al (2009) pygo2 expands mammary progenitor cells by facilitating histone H3K4methylation [J]. J. Cell Biol 185(5):811–826CrossRefGoogle Scholar
  51. 51.
    Sparrow J, Hughes SM, Segalat L (2008) Other model organisms for sarcomeric muscle diseases[J]. Adv Exp Med Biol 642:192–206CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Perkins AD1, Tanentzapf G1 (2014) An ongoing role for structural sarcomeric components [J]. PLoS One 9(6):e99362CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Delon I, Brown NH (2007) Integrins and the actin cytoskeleton[J]. Curr Opin Cell Biol 19:43–50CrossRefPubMedGoogle Scholar
  54. 54.
    Chen X, Li Z, Feng Z, Wang J, Ouyang C et al (2006) Integrin-linked kinase induces both senescence-associated alterations and extracellular fibronectin assembly in aging cardiac fibroblasts[J]. JGerontol A Biol Sci Med Sci 61:1232–1245CrossRefGoogle Scholar
  55. 55.
    White DE, Coutu P, Shi YF, Tardif JC, Nattel S, St Arnaud R, Dedhar S, Muller WJ (2006) Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure[J]. Genes Dev 20:2355–2360CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Nishimura M1, Kumsta C, Kaushik G, Diop SB et al (2014) A dual role for integrin-linked kinase and b1-integrin in modulating cardiac aging [J].Aging. Cell 13(3):431–440Google Scholar
  57. 57.
    Larjava H, Plow EF, Wu C (2008) Kindlins: essential regulators of integrin signalling and cell-matrix adhesion[J]. EMBO Rep 9:1203–1208CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Dowling JJ, Gibbs E, Russell M, Goldman D, Minarcik J et al (2008) Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function[J]. Circ Res 102:423–431CrossRefPubMedGoogle Scholar
  59. 59.
    Catterson JH1, Heck MM, Hartley PS (2013) Fermitins, the orthologs of mammalian kindlins, regulate the development of a functional cardiac syncytium in Drosophila melanogaster [J]. PLoS One 8(5):e62958CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Olson TM, Illenberger S, Kishimoto NY et al (2002) Meta vinculin mutations alter actin interaction in dilated cardiomyopathy[J]. Circulation 105:431–437CrossRefPubMedGoogle Scholar
  61. 61.
    Kaushik G, Spenlehauer A, Sessions AO, Trujillo AS et al (2015) Vinculin network–mediated cytoskeletal remodeling[J]. Sci Transl Med 7(292):292ra99CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Ma S, Ma CC (2011) Recent development in pleiotropic effects of statins on cardiovascular disease through regulation of transforming growth factor-beta superfamily[J]. Cytokine Growth Factor Rev 22:167–175PubMedGoogle Scholar
  63. 63.
    Spindler SR, Li R, Dhahbi JM, Yamakawa A et al (2015) Statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation[J]. PLoS One 7(6):e39581CrossRefGoogle Scholar
  64. 64.
    Laribee RN, Shibata Y, Mersman DP, Collins SR et al (2007) CCR4/NOT complex associates with the proteasome and regulates histone methylation[J]. Proc Natl Acad Sci U S A 104:5836–5841CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Tucker M, Valencia-Sanchez MA, Staples RR, Chen J, Denis CL, Parker R (2001) The transcription factor associated Ccr4 and Caf1 proteins are components of the major cytoplasmic mRNA deadenylase in Saccharomyces cerevisiae[J]. Cell 104:377–386CrossRefPubMedGoogle Scholar
  66. 66.
    Behm-Ansmant I, Rehwinkel J, Doerks T, Stark A, Bork P, Izaurralde E (2006) mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes[J]. Genes Dev 20:1885–1898CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Neely GG, Kuba K, Cammarato A, Isobe K et al (2010) A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function. [J]. Cell 141(6):142–153CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Albert TK, Lemaire M, van Berkum NL, Gentz R, Collart MA, Timmers HT (2000) Isolation and characterization of human orthologs of yeast CCR4-NOT complex subunits. Nucleic Acids Res 28:809–817CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Brosel S, Yang H, Tanji K, Bonilla E, Schon EA (2010) Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues: implications for human mitochondrial disease[J]. Am J Pathol 177:2541–2548CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Martínez-Morentin L, Martínez L, Piloto S et al (2015) Cardiac deficiency of single cytochrome oxidase assembly factor scox induces p53-dependent apoptosis in a Drosophila cardiomyopathy model[J]. Hum Mol Genet 24(13):3608–3622PubMedPubMedCentralGoogle Scholar
  71. 71.
    Li A, Zhou C, Moore J, Zhang P, Tsai TH et al (2011) Changes in the expression of the alzheimer’s disease-associated presenilin gene in Drosophila heart leads to cardiac dysfunction[J]. Curr Alzheimer Res 8:313–322CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Lanska DJ, Lavine L, Lanska MJ, Schoenberg BS (1988) Huntington’s disease mortality in the United States[J]. Neurology 38:769–772CrossRefPubMedGoogle Scholar
  73. 73.
    Mihm MJ, Amann DM, Schanbacher BL, Altschuld RA, Bauer JA et al (2007) Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease[J]. Neurobiol Dis 25(2):297–308CrossRefPubMedGoogle Scholar
  74. 74.
    Melkani GC, Trujillo AS, Ramos R, Bodmer R, Bernstein SI, Ocorr K (2013) Huntington’s disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart[J]. PLoS Genet 9:e1004024CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Zesiewicz TA, Strom JA, Borenstein AR, Hauser RA et al (2004) Heart failure in Parkinson’s disease: analysis of the United States medicare current beneficiary survey[J]. Parkinsonism Relat Disord 10:417–420CrossRefPubMedGoogle Scholar
  76. 76.
    Bhandari P1, Song M, Chen Y, Burelle Y, Dorn GW (2014) Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts and its containment by suppressing mitofusin[J]. Circ Res 114(2):257–265CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2016

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.The Center for Heart Development, Key Lab of MOE for Development Biology and Protein Chemistry, College of Life SciencesHunan Normal UniversityChangshaChina
  2. 2.Center for Cancer and Immunology ResearchChildren’s National Medical CenterWashingtonUSA

Personalised recommendations