Abstract 80: PI3Kα Regulates Biomechanical Stress-induced Cytoskeletal Remodeling: A Critical Role of Gelsolin

Abstract

Background: Biomechanical stress and cytoskeletal remodeling are key determinants in pressure overload-induced heart failure. Class Ia phosphoinositide 3-kinases (PI3Ks) mediate a variety of cellular activities, in response to agonist binding to cell-surface receptors, by generating the phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) phosphoinositide lipid. Gelsolin is a Ca 2+ - and phosphoinositide-regulated actin filament severing and capping protein that is upregulated in failing human hearts and animal models of heart failure. Hypothesis: We hypothesize that PI3Kα regulates cytoskeletal remodeling through PIP 3 -mediated regulation of gelsolin. In addition, loss of gelsolin could attenuate the adverse cytoskeletal remodeling and result in increased resistance to the development of heart failure in response to pressure-overload. Methods and Results: Loss of p110α kinase activity, in two different transgenic models (PI3Kα dominant-negative (PI3KαDN) and cardiomyocyte-specific PI3Kα-null), resulted in dilated cardiomyopathy and markedly worsened cardiac dysfunction in response to transverse aortic constriction-induced pressure overload. Increased levels of mechanosensor proteins along with decreased F/G-actin ratio exhibited an uncoupling between cardiac mechanotransduction and cytoskeletal remodeling in p110α-null mice. Gelsolin activity was markedly increased in the p110α-null hearts in response to pressure-overload, whereas loss of gelsolin in PI3KαDN/gelsolin-null double mutant mice prevented the adverse cytoskeletal remodeling and preserved the cardiac function. In a murine model of chronic heart failure, loss of gelsolin prevented the pressure overload-induced cardiac dysfunction, fibrosis, and impaired cardiomyocyte contractility resulting in increased survival. Loss of gelsolin also mitigated the biomechanical stress-induced adverse cytoskeletal remodeling, via the attenuation of actin severing activity. Conclusions: We have identified a novel role of gelsolin as a mediator of adverse cytoskeletal remodeling leading to heart failure, where PI3Kα is a key regulator of gelsolin activity.