MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy

Stephan Lange (), Katja Gehmlich, Alexander S. Lun, Jordan Blondelle, Charlotte Hooper, Nancy D. Dalton, Erika A. Alvarez, Xiaoyu Zhang, Marie-Louise Bang, Yama A. Abassi, Cristobal G. dos Remedios, Kirk L. Peterson, Ju Chen () and Elisabeth Ehler ()
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Stephan Lange: School of Medicine, University of California
Katja Gehmlich: BHF Centre of Research Excellence Oxford, University of Oxford
Alexander S. Lun: School of Medicine, University of California
Jordan Blondelle: School of Medicine, University of California
Charlotte Hooper: BHF Centre of Research Excellence Oxford, University of Oxford
Nancy D. Dalton: School of Medicine, University of California
Erika A. Alvarez: School of Medicine, University of California
Xiaoyu Zhang: ACEA Biosciences
Marie-Louise Bang: Institute of Genetic and Biomedical Research, UOS Milan, National Research Council
Yama A. Abassi: ACEA Biosciences
Cristobal G. dos Remedios: Bosch Institute, University of Sydney
Kirk L. Peterson: School of Medicine, University of California
Ju Chen: School of Medicine, University of California
Elisabeth Ehler: BHF Centre of Research Excellence at King’s College London

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract MLP (muscle LIM protein)-deficient mice count among the first mouse models for dilated cardiomyopathy (DCM), yet the exact role of MLP in cardiac signalling processes is still enigmatic. Elevated PKCα signalling activity is known to be an important contributor to heart failure. Here we show that MLP directly inhibits the activity of PKCα. In end-stage DCM, PKCα is concentrated at the intercalated disc of cardiomyocytes, where it is sequestered by the adaptor protein CARP in a multiprotein complex together with PLCβ1. In mice deficient for both MLP and CARP the chronic PKCα signalling chain at the intercalated disc is broken and they remain healthy. Our results suggest that the main role of MLP in heart lies in the direct inhibition of PKCα and that chronic uninhibited PKCα activity at the intercalated disc in the absence of functional MLP leads to heart failure.

Date: 2016
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DOI: 10.1038/ncomms12120

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