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Nat Commun. 2014 Sep 11;5:4533. doi: 10.1038/ncomms5533.

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function.

Author information

1
Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
2
University Health Network, University of Toronto, Toronto, Ontario, Canada M5S 2J7.
3
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada M5S 3G9.
4
Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.
5
1] Program in Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
6
1] Program in Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3] Heart &Stroke Richard Lewar Centre of Excellence, Toronto, Ontario, Canada M5B 1W8.
7
Cell Adhesion Signaling Laboratory, Monash Institute of Medical Research, Monash University, Melbourne, Victoria 3800, Australia.
8
1] Department of Anesthesia and Pain Medicine, Division of Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 [2] Departments of Anesthesia and Biochemistry, Universtiy of Toronto, Toronto, Ontario, Canada M5S 2J7.

Abstract

Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca(2+)ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK(R211A)) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

PMID:
25208486
DOI:
10.1038/ncomms5533
[Indexed for MEDLINE]

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