Abstract
SUMMARYIn response to stress and extracellular signals, the heart undergoes a process called cardiac hypertrophy during which cardiomyocytes increase in size. If untreated, cardiac hypertrophy can progress to overt heart failure that causes significant morbidity and mortality. The identification of molecular signals that cause or modify cardiomyopathies is necessary to understand how the normal heart progresses to cardiac hypertrophy and heart failure. Receptor tyrosine kinase (RTK) signaling is essential for normal human cardiac function, and the inhibition of RTKs can cause dilated cardiomyopathies. However, neither investigations of activated RTK signaling pathways nor the characterization of hypertrophic cardiomyopathy in the adult fly heart has been previously described. Therefore, we developed strategies using Drosophila as a model to circumvent some of the complexities associated with mammalian models of cardiovascular disease. Transgenes encoding activated EGFRA887T, Ras85DV12 and Ras85DV12S35, which preferentially signal to Raf, or constitutively active human or fly Raf caused hypertrophic cardiomyopathy as determined by decreased end diastolic lumen dimensions, abnormal cardiomyocyte fiber morphology and increased heart wall thicknesses. There were no changes in cardiomyocyte cell numbers. Additionally, activated Raf also induced an increase in cardiomyocyte ploidy compared with control hearts. However, preventing increases in cardiomyocyte ploidy using fizzy-related (Fzr) RNAi did not rescue Raf-mediated cardiac hypertrophy, suggesting that Raf-mediated polyploidization is not required for cardiac hypertrophy. Similar to mammals, the cardiac-specific expression of RNAi directed against MEK or ERK rescued Raf-mediated cardiac hypertrophy. However, the cardiac-specific expression of activated ERKD334N, which promotes hyperplasia in non-cardiac tissues, did not cause myocyte hypertrophy. These results suggest that ERK is necessary, but not sufficient, for Raf-mediated cardiac hypertrophy.
Highlights
Cardiomyopathies are generally associated with a myocyte growth program that leads to an increase in the size of individual muscle cells
To understand how the normal heart progresses to cardiac hypertrophy and heart failure, the molecular signaling pathways and gene expression programs that together control the growth and differentiation of cardiomyocytes need to be studied in depth
Using optical coherence tomography, confocal microscopy and histological analysis, the authors show that fly cardiomyocytes become enlarged and the volume of cardiac lumen decreases in response to the cardiac-specific expression of signals that emanate from EGFR through Ras, Raf, mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK)
Summary
Cardiomyopathies are generally associated with a myocyte growth program that leads to an increase in the size of individual muscle cells. Individuals who have cardiac hypertrophy and cardiomyopathies are predisposed to the development of heart failure (Vasan et al, 1997). Heart failure affects 5.7 million individuals in the United States, has an annual economic health care burden in excess of US$34 billion in the United States, is associated with significant morbidity and has a 5-year mortality rate of ~50% despite current pharmacological and device-based therapies (Roger et al, 2010). The development of new pharmaceutical agents to treat heart failure has been disappointing despite an increased understanding of the pathophysiology of cardiomyopathies. In response to a variety of stimuli, including RTK-mediated signals, the mammalian heart undergoes morphological changes that contribute to the development of dilated or hypertrophic cardiomyopathies (Heineke and Molkentin, 2006). Dilated cardiomyopathies are characterized by enlargement of the heart chambers, thinning of the heart walls and poor contractility of the myocardium
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