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

TY - JOUR

T1 - MLP and CARP are linked to chronic PKCα signaling in dilated cardiomyopathy

AU - Lange, Stephan

AU - Gehmlich, Katja

AU - Lun, Alexander S.

AU - Blondelle, Jordan

AU - Hooper, Charlotte

AU - Dalton, Nancy D

AU - Alvarez, Erika A.

AU - Zhang, Xiaoyu

AU - Bang, Marie-Louise

AU - Abassi, Yama A.

AU - dos Remedios, Cristobal G.

AU - Peterson, Kirk L

AU - Chen, Ju

AU - Ehler, Elisabeth

PY - 2016/6/29

Y1 - 2016/6/29

N2 - 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.

AB - 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.

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

U2 - 10.1038/ncomms12120

DO - 10.1038/ncomms12120

M3 - Article

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 12120

ER -