Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes.
Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes.
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DOI：
10.1083/jcb.201507018
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发表时间：
2016-02-15
期刊：
影响因子：
--
通讯作者：
Green KJ
中科院分区：
文献类型：
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作者：
Dubash AD;Kam CY;Aguado BA;Patel DM;Delmar M;Shea LD;Green KJ
新生心肌细胞中桥粒犰狳蛋白Plakophilin-2的缺失导致细胞骨架连接蛋白Desmoplakin的稳定性和表达降低，其导致TGF-β1/p38 MAPK信号级联的激活并诱导纤维化基因的表达。桥粒蛋白家族的成员是心脏复合区的组成部分，心脏复合区是一种负责心肌细胞之间机电耦合的混合连接复合体。在这项研究中，我们提供的证据表明，心肌细胞桥粒犰狳蛋白Plakophilin-2（PKP 2）的缺失提高了转化生长因子β1（TGF-β1）和p38丝裂原活化蛋白激酶（MAPK）信号转导，它们共同协调导致促纤维化基因表达增加的转录程序。重要的是，我们证明了桥粒斑蛋白（DP）的表达在PKP 2敲低后丢失，DP表达的恢复挽救了TGF-β1/p38 MAPK转录级联的激活。来自PKP 2杂合和DP条件性敲除小鼠模型的组织也表现出体内升高的TGF-β1/p38 MAPK信号传导和纤维化基因表达的诱导。因此，这些数据将PKP 2和DP确定为心肌细胞中桥粒依赖性TGF-β1/p38 MAPK信号传导的协调中心参与者，已知该途径在不同类型的心脏疾病中发挥作用，例如致心肌病或肥厚性心肌病。
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. 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.