Abstract 18956: Loss of Gelsolin Attenuates Pressure Overload Induced Heart Failure: Novel Role of Gelsolin in Cardiac Biomechanical Stress Induced Cytoskeletal Remodeling
Background: Biomechanical stress and cytoskeletal remodeling are key determinants in pressure-overload induced heart failure. Gelsolin (GSN) is a Ca2+ and polyphosphoinositide 4,5-biphosphate (PIP2)-regulated actin filament severing and capping protein, and is upregulated in failing human hearts and animal models of heart failure (HF).
Hypothesis: We hypothesize that loss of gelsolin will attenuate the adverse cytoskeletal remodeling and will lead to increased resistance to the development of HF in response to pressure-overload.
Methods and Results: Eight-week old male GSN null (GSNKO) mice and wildtype (WT) littermate control mice were subjected to transverse aortic constriction (TAC) induced pressure-overload. GSN expression was increased in response to 9 wks of pressure-overload in WT mice, which was associated with heart failure with reduced ejection fraction (EF). Loss of gelsolin resulted in preserved systolic function (EF: 54.6±2.07 in GSNKO-TAC vs 39.4±3.04 in WT-TAC; p0.05). Cardiomyocytes from WT LVs subjected to 9-wk TAC showed markedly decreased contractility and relaxation, which was preserved in cardiomyocytes isolated from GSNKO TAC LVs (FS: 7.06±0.51 in GSNKO-TAC vs 4.25±0.46 in WT-TAC; P<0.05). Biomechanical stress resulted in decreased N-cadherin and β-catenin in the WT hearts with unchanged F-actin/G-actin ratio, an indicator of actin polymerization, suggesting a defect in cardiac mechanotransduction and cytoskeletal remodeling. In contrast, GSNKO hearts showed preserved N-cadherin/β-catenin levels along with increased F-actin/G-actin ratio, suggestive of adaptive remodeling in response to biomechanical stress.
Conclusions: These data demonstrates that loss of gelsolin attenuates pressure-overload induced heart failure. We identified a novel role of gelsolin as a mediator of biomechanical stress induced adverse cytoskeletal remodeling and HF.
Author Disclosures: V.B. Patel: None. P. Zhabyeyev: None. R. Basu: None. Z. Kassiri: None. G.Y. Oudit: None.
- © 2014 by American Heart Association, Inc.