P493Sprouty1 regulates cardiac homeostasis by negatively regulating the receptor tyrosine kinase pathways in heart

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Until recently much effort has been spent on deciphering the signaling pathways promoting cardiac hypertrophy with comparable little interest for negative regulators of cardiac hypertrophy. Receptor tyrosine kinases (RTK) act as transducers of growth factors and are known to play a critical role in cardiogenesis and cardiac homeostasis. As powerful regulators of multiple cellular functions RTK pathways have to be tightly regulated to limit the strength, duration and range of signaling. To a large extent, this role is carried out by Sprouty (SPRY) proteins that negatively modulate RTK pathways. We have previously described that SPRY1 (a member of the SPRY family) expression is downregulated in the murine and human failing heart. However, the role of SPRY1 in the heart still remains unknown. Therefore, the overall goal of our study is to elucidate the function of SPRY1 in the heart.


To investigate the potential role of SPRY1 in the heart, we studied the cardiac phenotype of Spry1-deficient mice (Spry1-/-). By echocardiography analysis, we found that 1 month-old mice with Spry1 global genetic ablation have normal heart weight and cardiac function compared to control Spry1 + / + animals. However, we uncovered that Spry1-/- mice display pronounced cardiac hypertrophy without fibrosis at 2 months of age (Left ventricular mass: 108 mg ± 21 in Spry1-/- mice vs 73 mg ± 9 in littermate Spry1 + / + control, n=5-6) associated with a significant alteration of their cardiac function (Fractional shortening: 19% ± 5 in Spry1-/- mice vs 29% ± 1 in littermate Spry1 + / + control), demonstrating that SPRY1 is necessary to maintain cardiac homeostasis in adult mice. Furthermore, by isolating adult cardiomyocytes (CMs), we found that Spry1-/- CMs surface area is significantly increased compared to Spry1 + / + CMs (1253 µm2 ± 37 for Spry1-/- CMs vs 950 ± 40 µm2 for Spry1 + / + CMs, n=3), suggesting that the hypertrophic phenotype observed in Spry1-/- mice is mainly due to an increase of their CMs size.


Our results reveal for the first time that SPRY1, a negative feedback regulator of the RTK pathways, controls cardiac homeostasis. Determination of the exact mode of action of SPRY1 within the heart in resting as well as in pathological conditions is currently under investigation.

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