title: Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent 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.
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Department of Biology, Furman University, Greenville SC 29613.
authors: Adi D
authors: AD
authors: Dubash
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors: Chen Y
authors: CY
authors: Kam
authors: Department of Biomedical Engineering, Northwestern University, Evanston IL 60208 Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago IL 60611.
authors: Brian A
authors: BA
authors: Aguado
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors: Dipal M
authors: DM
authors: Patel
authors: New York University School of Medicine, New York, NY 10016.
authors: Mario
authors: M
authors: Delmar
authors: Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48105.
authors: Lonnie D
authors: LD
authors: Shea
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 kgreen@northwestern.edu.
authors: Kathleen J
authors: KJ
authors: Green
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005355:Fibrosis; D005786:Gene Expression Regulation; D005838:Genotype; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D051191:Plakophilins / Q000172:deficiency* / Q000235:genetics; D055550:Protein Stability; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051180:Desmoplakins; C495295:Dsp protein, mouse; D018836:Inflammation Mediators; C495338:Pkp2 protein, mouse; C542110:Pkp2 protein, rat; D051191:Plakophilins; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases