PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease

Vaibhav B. Patel, Pavel Zhabyeyev, Xueyi Chen, Faqi Wang, Manish Paul, Dong Fan, Brent A. McLean, Ratnadeep Basu, Pu Zhang, Saumya Shah, John F. Dawson, W. Glen Pyle, Mousumi Hazra, Zamaneh Kassiri, Saugata Hazra, Bart Vanhaesebroeck, Christopher A. McCulloch and Gavin Y. Oudit ()
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Vaibhav B. Patel: Division of Cardiology, Department of Medicine
Pavel Zhabyeyev: Division of Cardiology, Department of Medicine
Xueyi Chen: Division of Cardiology, Department of Medicine
Faqi Wang: Division of Cardiology, Department of Medicine
Manish Paul: North Orissa University
Dong Fan: University of Alberta
Brent A. McLean: University of Alberta
Ratnadeep Basu: University of Alberta
Pu Zhang: University of Alberta
Saumya Shah: Division of Cardiology, Department of Medicine
John F. Dawson: University of Guelph
W. Glen Pyle: University of Guelph
Mousumi Hazra: Gurukula Kangri University
Zamaneh Kassiri: University of Alberta
Saugata Hazra: Indian Institute of Technology
Bart Vanhaesebroeck: University College London, London
Christopher A. McCulloch: University of Toronto
Gavin Y. Oudit: Division of Cardiology, Department of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07812-8

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