PI3K\u03b1-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease

Vaibhav B Patel,Faqi Wang,Christopher A Mcculloch,Pu Zhang,Zamaneh Kassiri,Dong Fan,Ratnadeep Basu,Mousumi Hazra,W Glen Pyle,Pavel Zhabyeyev,Gavin Y Oudit,Manish Paul,Saugata Hazra,John F Dawson,Bart Vanhaesebroeck,Saumya Shah,Xueyi Chen,Brent A Mclean

doi:10.1038/s41467-018-07812-8

Abstract

Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prevents biomechanical stress-induced adverse cytoskeletal remodeling and heart failure in mice. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Accordingly, loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity.

Highlights

Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury
We found that disease progression in human dilated cardiomyopathy (DCM), as measured by LV ejection fraction (LVEF), is linked to greater gelsolin actin-depolymerizing activity (Fig. 1b and Supplementary Fig. 1a)
Given that gelsolin is a major mediator of actin cytoskeleton remodeling, we hypothesized that this protein could be a critical mediator of Heart failure (HF) (Fig. 1h and Supplementary Fig. 2a)

Summary

Introduction

Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity. Gelsolin is a Ca2+-regulated actin filament severing and capping protein, that is widely expressed in a variety of tissues including the heart, brain, immune cells, and various cancer tissues[7]. Using a combination of explanted human and canine hearts, genetic mouse models, computer modeling, and biochemical studies, we identify gelsolin-mediated actin cytoskeletal remodeling as a critical response to biomechanical stress-induced mechanotransduction and in the pathogenesis of HF. We show that gelsolin’s severing activity is inhibited by the PI3Kα product, PIP3, in response to stress-induced cardiac mechanotransduction thereby identifying a central regulatory mechanism of gelsolin’s action. We highlight the importance of biomechanical stressinduced cytoskeletal remodeling as an essential response involved in adaptive cardiac remodeling

Methods

Results

Conclusion