The Ski-Zeb2-Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype
The Ski-Zeb2-Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype
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DOI：
10.1242/jcs.126722
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
Dixon, Ian M. C.
中科院分区：
文献类型：
--
作者：
Cunnington, Ryan H.;Northcott, Josette M.;Dixon, Ian M. C.
心脏纤维化与成纤维细胞到肌成纤维细胞的表型转化和增殖有关，但其背后的机制尚不清楚。Ski是肌成纤维细胞中tgf - β - smad信号的负调节因子，并可能将肌成纤维细胞表型重定向回成纤维细胞。Meox2可以改变tgf - β介导的细胞过程，并被Zeb2抑制。在这里，我们研究了Ski是否通过去抑制Meox2的表达来减少肌成纤维细胞表型，并通过抑制Zeb2的表达来减少功能。我们发现，在成纤维细胞向肌成纤维细胞的表型转化过程中，Meox1和Meox2 mRNA以及Meox2蛋白的表达减少。过表达Meox2可使肌成纤维细胞转变为成纤维细胞，而Meox2 dna结合突变体对肌成纤维细胞表型没有影响。过表达Ski可部分恢复心肌成纤维细胞中Meox2 mRNA的表达水平。在表型转化过程中Zeb2的表达增加，Ski过表达降低了首代肌成纤维细胞中Zeb2的表达。此外，心肌梗死后疤痕组织中Meox2表达降低，而Zeb2蛋白表达升高。因此，Ski通过上调Meox2的表达抑制Zeb2来调节心肌成纤维细胞的表型和功能。这种级联可能调节心肌成纤维细胞表型，并为心脏纤维化的治疗提供了治疗选择。
Cardiac fibrosis is linked to fibroblast-to-myofibroblast phenoconversion and proliferation but the mechanisms underlying this are poorly understood. Ski is a negative regulator of TGF-beta-Smad signaling in myofibroblasts, and might redirect the myofibroblast phenotype back to fibroblasts. Meox2 could alter TGF-beta-mediated cellular processes and is repressed by Zeb2. Here, we investigated whether Ski diminishes the myofibroblast phenotype by de-repressing Meox2 expression and function through repression of Zeb2 expression. We show that expression of Meox1 and Meox2 mRNA and Meox2 protein is reduced during phenoconversion of fibroblasts to myofibroblasts. Overexpression of Meox2 shifts the myofibroblasts into fibroblasts, whereas the Meox2 DNA-binding mutant has no effect on myofibroblast phenotype. Overexpression of Ski partially restores Meox2 mRNA expression levels to those in cardiac fibroblasts. Expression of Zeb2 increased during phenoconversion and Ski overexpression reduces Zeb2 expression in first-passage myofibroblasts. Furthermore, expression of Meox2 is decreased in scar following myocardial infarction, whereas Zeb2 protein expression increases in the infarct scar. Thus Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by upregulating the expression of Meox2. This cascade might regulate cardiac myofibroblast phenotype and presents therapeutic options for treatment of cardiac fibrosis.