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Raf-mediated cardiac hypertrophy in adult Drosophila
Lin Yu1, Joseph Daniels, Alex E Glaser
1Duke University Medical Center, 321 Sands Building, Research Drive, Durham, NC 27710, USA.
Insights
Researchers used Drosophila to study cardiac hypertrophy, a heart condition. They found that activated Raf signaling causes heart muscle cells to enlarge, but ERK is necessary, not sufficient, for this process.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Drosophila melanogaster as a model organism
Background:
- Cardiac hypertrophy, an enlargement of cardiomyocytes, can lead to heart failure.
- Receptor tyrosine kinase (RTK) signaling is crucial for heart function; its inhibition causes dilated cardiomyopathies.
- Understanding molecular signals in cardiac hypertrophy is vital for treating heart disease.
Purpose of the Study:
- To investigate activated RTK signaling pathways in cardiac hypertrophy.
- To characterize hypertrophic cardiomyopathy in the adult Drosophila heart.
- To identify molecular mechanisms underlying cardiac hypertrophy using a fly model.
Main Methods:
- Utilized Drosophila melanogaster as a model system for cardiovascular disease.
- Generated transgenes for activated EGFR, Ras85D, and Raf signaling components.
- Employed RNA interference (RNAi) to study gene function, including fizzy-related (Fzr) and MEK/ERK pathways.
Main Results:
- Activated Raf signaling induced hypertrophic cardiomyopathy in fly hearts, characterized by reduced lumen dimensions and thickened walls.
- Raf-mediated cardiac hypertrophy occurred without changes in cardiomyocyte number but with increased ploidy.
- Inhibition of MEK or ERK rescued Raf-mediated cardiac hypertrophy, while activated ERK alone did not induce hypertrophy.
Conclusions:
- ERK signaling is essential but not sufficient for Raf-mediated cardiac hypertrophy.
- Raf-induced polyploidization of cardiomyocytes is not required for cardiac hypertrophy.
- Drosophila serves as a valuable model for studying conserved mechanisms of cardiac hypertrophy.
Abstract:
In 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 EGFR(A887T), Ras85D(V12) and Ras85D(V12S35), 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 ERK(D334N), 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.
