title: MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy.
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.
authors.affiliation: School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
authors.forename: Stephan
authors.identifier: 0000-0001-9361-6602
authors.initials: S
authors.lastname: Lange
authors.affiliation: BHF Centre of Research Excellence Oxford, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Gehmlich
authors.affiliation: School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Lun
authors.affiliation: School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Blondelle
authors.affiliation: BHF Centre of Research Excellence Oxford, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hooper
authors.affiliation: School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.affiliation: School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
authors.forename: Erika A
authors.initials: EA
authors.lastname: Alvarez
authors.affiliation: ACEA Biosciences, 6779 Mesa Ridge Rd #100, San Diego, CA-92121, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Genetic and Biomedical Research, UOS Milan, National Research Council, Rozzano (Milan) 20089, Italy.|Humanitas Clinical and Research Center, Rozzano (Milan) 20089, Italy.
authors.forename: Marie-Louise
authors.identifier: 0000-0001-8859-5034
authors.initials: ML
authors.lastname: Bang
authors.affiliation: ACEA Biosciences, 6779 Mesa Ridge Rd #100, San Diego, CA-92121, USA.
authors.forename: Yama A
authors.initials: YA
authors.lastname: Abassi
authors.affiliation: Bosch Institute, Department of Anatomy, University of Sydney, Sydney 2006, Australia.
authors.forename: Cristobal G
authors.initials: CG
authors.lastname: Dos Remedios
authors.affiliation: School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: BHF Centre of Research Excellence at King's College London, Cardiovascular Division and Randall Division of Cell and Molecular Biophysics, London SE1 1UL, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ehler
mesh_terms: D000818:Animals; D019556:COS Cells; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004926:Escherichia coli; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C491304:ANKRD1 protein, human; C104844:Ankrd1 protein, mouse; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C090114:cysteine and glycine-rich protein 3; D051571:Protein Kinase C-alpha