Abstract 17196: Sprouty1 Regulates Cardiac Homeostasis by Modulating Cardiac Fibroblast Receptor Tyrosine Kinase Signaling
Purpose: Receptor tyrosine kinases (RTK) act as transducers of growth factors and are known to play a critical role in cardiac development and homeostasis. As powerful regulators of multiple cellular functions RTK pathways are tightly regulated to limit the strength, duration and range of signaling. Sprouty (SPRY) proteins are major repressors of RTK pathways. Until now, the functional role of SPRY1 in the heart remains unknown. The overall goal of this study is to elucidate the function of SPRY1 in the heart.
Results: Using immunofluorescence, we found SPRY1 to be specifically expressed in the epicardium and cardiac fibroblasts (CFs) but not in cardiomyocytes of the embryonic or adult murine heart. To investigate the potential role of SPRY1 in the heart, we next studied the cardiac phenotype of global Spry1-deficient mice (Spry1-/-). We found that 1 and 2 month-old Spry1-/- mice have normal heart weight and cardiac function compared to control Spry1+/+ (n=8). However, Spry1-/- mice displayed pronounced cardiac hypertrophy at 4 months of age (heart weight to tibia length ratio: 12.2 ± 1.3 in Spry1-/- mice vs. 8.9 ± 0.6 in littermate Spry1+/+ controls, n=5-7, p=0.03) associated with a significant alteration of their cardiac function as measured by echocardiography (fractional shortening: 19.3% ± 1.6 in Spry1-/- mice vs. 24.5% ± 2.9 in littermate Spry1+/+, p≤0.05), demonstrating that SPRY1 is required to maintain cardiac homeostasis. Using Cre-lox technology, we next generated cardiac fibroblast-specific Spry1 knockout (CF-specific Spry1 KO) mice by deleting Spry1 solely in the epicardium and derivatives (mostly CFs). By qPCR, we showed that Spry1 expression was reduced by 85% in isolated adult CFs of CF-specific Spry1 KO mice compared to CFs from littermate control mice (n=3). Interestingly, CF-specific Spry1 KO mice exhibited significant cardiac hypertrophy compared to littermate controls (heart weight: 200mg ± 13 vs. 160mg ± 4, n=5, p=0.01), demonstrating that SPRY1 in CFs regulates cardiac growth.
Conclusion: Our results reveal for the first time that SPRY1 in CFs controls cardiac homeostasis. Deciphering the exact mechanism of action of SPRY1 within the heart in resting as well as in pathological conditions is currently under progress.
- © 2012 by American Heart Association, Inc.