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Nat Commun. 2016 Jun 29;7:12120. doi: 10.1038/ncomms12120.

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

Author information

1
School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
2
BHF Centre of Research Excellence Oxford, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
3
ACEA Biosciences, 6779 Mesa Ridge Rd #100, San Diego, CA-92121, USA.
4
Institute of Genetic and Biomedical Research, UOS Milan, National Research Council, Rozzano (Milan) 20089, Italy.
5
Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
6
Bosch Institute, Department of Anatomy, University of Sydney, Sydney 2006, Australia.
7
BHF Centre of Research Excellence at King's College London, Cardiovascular Division and Randall Division of Cell and Molecular Biophysics, London SE1 1UL, UK.

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.

PMID:
27353086
PMCID:
PMC4931343
DOI:
10.1038/ncomms12120
[Indexed for MEDLINE]
Free PMC Article

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