Molecular mechanisms of heart failure: insights from Drosophila

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.