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

Alexandra Traister1, Mark Li1, Shabana Aafaqi1

  • 1Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.

Nature Communications
|September 12, 2014
PubMed

Insights

Integrin-linked kinase (ILK) regulates heart muscle function by controlling calcium handling proteins. A specific ILK mutation enhances cardiac function, offering a potential therapeutic target for dilated cardiomyopathy (DCM).

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Dilated cardiomyopathy (DCM) severely impairs heart function, with no effective mechanism-based therapies available.
  • The process of mechanotransduction, how mechanical forces change cardiac contractility, is poorly understood in normal and diseased hearts.

Purpose of the Study:

  • To investigate the role of integrin-linked kinase (ILK) in mediating cardiomyocyte mechanotransduction in the human heart.
  • To explore the potential of modulating ILK activity for treating DCM.

Main Methods:

  • Investigated the interaction between ILK, sarcoplasmic/endoplasmic reticulum Ca(2+)ATPase isoform 2a (SERCA-2a), and phospholamban (PLN) in human cardiac tissue.
  • Utilized a non-oncogenic ILK mutation (ILK(R211A)) to assess its impact on cardiac function.

Main Results:

  • Identified ILK as a key mediator of cardiomyocyte force transduction through regulation of SERCA-2a and phospholamban (PLN) phosphorylation.
  • Demonstrated that the ILK(R211A) mutation enhances global cardiac function by modulating the SERCA-2a/PLN module.

Conclusions:

  • ILK links mechanical input to cardiac contractility via the SERCA-2a/PLN pathway.
  • Targeting ILK and its interaction with SERCA-2a/PLN presents a novel therapeutic strategy to rescue impaired mechanotransduction in DCM.

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