Abstract 3433: Cardiac Myocyte-specific Caveolin-3 Overexpression Modulates ERK/EGFR Signaling and Attenuates Cardiac Hypertrophy
Introduction: The localization and organization of signaling molecules involved in cardiac hypertrophy and remodeling are poorly understood. Caveolae, invaginations of the sarcolemma and enriched in the protein caveolin (Cav), localize signaling molecules involved in cardiac hypertrophy and remodeling. Cav-3, which is unique to myocyte caveolae, inhibits extracellular signal-regulated kinase (ERK) phosphorylation in vitro and binds the epidermal growth factor (EGF) receptor. We hypothesized that cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) would modulate ERK signaling via direct interaction and alteration in EGF receptor signaling and would attenuate cardiac hypertrophy.
Methods: Transgenic mice with cardiac myocyte-specific Cav-3 OE (generated using an α-myosin heavy chain promoter) and littermate controls (C) were subjected to transverse aortic constriction (TAC) for 4 weeks. Echocardiography, histology and molecular analysis were performed. Cardiac myocytes were isolated and stimulated with phenylephrine (Phe) and EGF to assess ERK activity via activation of Gq and EGF receptors, respectively.
Results: Cav-3OE mice had reduced heart weight/tibia length ratio post-TAC compared to C (9.9±0.8 vs. 12.9±0.5 mg/mm; n=8; P<0.05) and decreased myocyte cross sectional area compared to C (203±8 vs. 327±17 μm2/cell; n=7; P<0.001). Cav-3 OE and C mice had similar fractional shortening (FS) pre-TAC but post-TAC, Cav-3 OE had greater FS compared to C (29.2±3.2 vs. 20.8±3.0%; n=8–9; P<0.05). Fibrosis, as assessed by trichrome stain, was decreased in Cav-3 OE compared to C mice. Post-TAC, pERK expression in cardiac homogenates was decreased in Cav3-OE mice vs. C. In vitro, pERK had, similar expression in the two groups in response to Phe, but pERK was expressed at higher levels in Cav3-OE myocytes in response to EGF receptor simulation.
Conclusion: These results show that cardiac-specific Cav-3 OE alters ERK/EGFR signaling in cardiac myocytes, producing a phenotype with blunted cardiac hypertrophy and preserved cardiac function post-TAC. This suggests that cardiac myocyte-specific Cav-3 OE may provide a novel approach to improve cardiac function in pathological cardiac hypertrophy and remodeling.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).