Plakophilin-2 loss promotes TGF-β1/p38 MAPKdependent fibrotic gene expression in cardiomyocytes

Adi D. Dubash; Chen Y. Kam; Brian A. Aguado; Dipal M. Patel; Mario Delmar; Lonnie D. Shea; Kathleen J. Green

doi:10.1083/jcb.201507018

Plakophilin-2 loss promotes TGF-β1/p38 MAPKdependent fibrotic gene expression in cardiomyocytes

Adi D. Dubash, Chen Y. Kam, Brian A. Aguado, Dipal M. Patel, Mario Delmar, Lonnie D. Shea, Kathleen J. Green^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

84 Scopus citations

Abstract

Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.

Original language	English (US)
Pages (from-to)	425-438
Number of pages	14
Journal	Journal of Cell Biology
Volume	212
Issue number	4
DOIs	https://doi.org/10.1083/jcb.201507018
State	Published - 2016

Funding

Imaging was performed at the Northwestern University Cell Imaging Facility supported by National Cancer Institute grant CCSG P30CA060553 (Robert H. Lurie Comprehensive Cancer Center). Sequencing services were performed at the Northwestern University Genomics Core Facility. This work was supported by National Institutes of Health grants R01 AR041836 and AR43380 and partial support from grant CA122151 and the J.L. Mayberry Endowment (to K.J. Green), National Institutes of Health grants NIH-HL106632 and NIH-GM057691 (to M. Delmar), and a Fondation Leducq Transatlantic Network grant (to M. Delmar and K.J. Green). A. Dubash was supported by American Heart Association postdoctoral fellowship 11POST7380001, C.Y. Kam was supported by American Heart Association predoctoral fellowship 15PRE25560138, and B.A. Aguado was supported by a National Science Foundation Graduate Research Fellowship.

ASJC Scopus subject areas

Cell Biology

Access to Document

10.1083/jcb.201507018

Cite this

@article{faf154d7fabd4c72bed834bc975709b5,

title = "Plakophilin-2 loss promotes TGF-β1/p38 MAPKdependent fibrotic gene expression in cardiomyocytes",

abstract = "Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.",

author = "Dubash, {Adi D.} and Kam, {Chen Y.} and Aguado, {Brian A.} and Patel, {Dipal M.} and Mario Delmar and Shea, {Lonnie D.} and Green, {Kathleen J.}",

note = "Publisher Copyright: {\textcopyright} 2016 Newell-Litwa.",

year = "2016",

doi = "10.1083/jcb.201507018",

language = "English (US)",

volume = "212",

pages = "425--438",

journal = "Journal of Cell Biology",

issn = "0021-9525",

publisher = "Rockefeller University Press",

number = "4",

}

TY - JOUR

T1 - Plakophilin-2 loss promotes TGF-β1/p38 MAPKdependent fibrotic gene expression in cardiomyocytes

AU - Dubash, Adi D.

AU - Kam, Chen Y.

AU - Aguado, Brian A.

AU - Patel, Dipal M.

AU - Delmar, Mario

AU - Shea, Lonnie D.

AU - Green, Kathleen J.

PY - 2016

Y1 - 2016

N2 - Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.

AB - Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.

UR - http://www.scopus.com/inward/record.url?scp=84959535607&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959535607&partnerID=8YFLogxK

U2 - 10.1083/jcb.201507018

DO - 10.1083/jcb.201507018

M3 - Article

C2 - 26858265

AN - SCOPUS:84959535607

SN - 0021-9525

VL - 212

SP - 425

EP - 438

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 4

ER -

Plakophilin-2 loss promotes TGF-β1/p38 MAPKdependent fibrotic gene expression in cardiomyocytes

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this