MLP and CARP are linked to chronic PKCα signaling 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, Elisabeth Ehler

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57 Citations (Scopus)
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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 signaling processes is still enigmatic. Elevated PKCα signaling 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 disk 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 signaling chain at the intercalated disk 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 disk in the absence of functional MLP leads to heart failure.
Original languageEnglish
Article number12120
Number of pages11
JournalNature Communications
Volume7
Issue number1
Early online date29 Jun 2016
DOIs
Publication statusPublished - 29 Jun 2016

Keywords

  • intercalated disk, dilated cardiomyopathy, CSRP3, MARP, ANKRD1, ANKRD2, heart failure, PKC

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