Molecular mechanisms of heart failure: insights from Drosophila

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.

TRP Channels Expression Profile in Human End-Stage Heart Failure

“…Heart failure (HF) is a culmination of different pathophysiological conditions on heart muscle which cause progressive worsening of heart function [1]. HF is usually preceded by chronic cardiac stress that could be the result of a cardiac injury (e.g., myocardial infarct, hypertension, valvular heart disease) and leads to structural changes, such as left ventricle hypertrophy, to maintain physiologic heart output [2,3].…”

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

“…We modeled these mutations in the Drosophila Lamin C gene (hereafter referred as LamC ) and assayed for effects on the fruit fly heart. Mechanisms of cardiac development and function are shared between Drosophila and humans (Diop & Bodmer, 2015; Melkani et al., 2013; Zhu et al., 2017). Furthermore, Drosophila has successfully been used to identify the genetic basis of cardiac deterioration that arises due to aging and metabolic dysregulation (Diop & Bodmer, 2015; Gill, Le, Melkani & Panda, 2015; Melkani et al., 2013).…”

<p>Carvedilol Alters Circulating MiR-1 and MiR-214 in Heart Failure</p>

“…As a consequence, the expression of oncogenes is increased, while the expression of normal and mature genes decreases leading to cardiac hypertrophy and/or remodeling, a pathological status that ultimately causes further damage to the failing cardiomyocytes, thus perpetuating the impaired cardiac function. 39 Compelling evidence points at the role of miRNAs in the regulation of cardiac remodeling and advocates the role of these small molecules as potential therapeutic biomarkers in HF. 40 – 42 In agreement with such findings, our results showed that miR-214 and miR-1 expressions were significantly upregulated in sera of patients with systolic HF who were treated with carvedilol.…”