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

Authors :
Adi D. Dubash
Lonnie D. Shea
Brian A. Aguado
Kathleen J. Green
Dipal M. Patel
Mario Delmar
Chen Y. Kam
Source :
The Journal of Cell Biology, The Journal of Experimental Medicine
Publication Year :
2016
Publisher :
Rockefeller University Press, 2016.

Abstract

Loss of the desmosome armadillo protein Plakophilin-2 in neonatal cardiomyocytes results in decreased stability and expression of the cytoskeletal linker protein Desmoplakin, which causes activation of a TGF-β1/p38 MAPK signaling cascade and induces expression of fibrotic genes.<br />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.

Details

ISSN :
15409538 and 00221007
Volume :
213
Database :
OpenAIRE
Journal :
The Journal of Experimental Medicine
Accession number :
edsair.doi.dedup.....5074401ccb4689316882a74045b3afd4
Full Text :
https://doi.org/10.1084/jem.2133oia12