Pathologic Regulation of Collagen I by an Aberrant Protein Phosphatase 2A/Histone Deacetylase C4/MicroRNA-29 Signal Axis in Idiopathic Pulmonary Fibrosis Fibroblasts
Pathologic Regulation of Collagen I by an Aberrant Protein Phosphatase 2A/Histone Deacetylase C4/MicroRNA-29 Signal Axis in Idiopathic Pulmonary Fibrosis Fibroblasts
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DOI：
10.1165/rcmb.2014-0150oc
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发表时间：
2015-09-01
影响因子：
6.4
通讯作者：
Henke, Craig A.
中科院分区：
文献类型：
--
作者：
Khalil, Wajahat;Xia, Hong;Henke, Craig A.
特发性肺纤维化（IPF）的特征在于成纤维细胞的持续扩张，在肺泡壁内沉积I型胶原并闭塞肺泡气腔。microRNA（miR）-29是胶原蛋白表达的有效调节剂。在IPF中，miR-29水平较低，而I型胶原蛋白表达较高。然而，抑制IPF中miR-29和I型胶原表达增加的机制仍不清楚。在这里，我们表明，当IPF成纤维细胞接种在聚合的I型胶原蛋白上时，miR-29 c水平受到抑制，I型胶原蛋白表达较高。相比之下，在对照成纤维细胞中，miR-29 c高，I型胶原蛋白表达低。我们证明了在IPF成纤维细胞与聚合胶原相互作用期间抑制miR-29的机制涉及蛋白磷酸酶（PP）2A功能的不适当降低，导致组蛋白脱乙酰酶（HDA）C4磷酸化和HDAC 4核转位减少。我们证明，在IPF成纤维细胞中过表达HDAC 4可恢复miR-29 c水平并降低I型胶原蛋白表达，而在对照成纤维细胞中敲低HDAC 4可抑制miR-29 c水平并增加I型胶原蛋白表达。我们的数据表明，IPF成纤维细胞与聚合的I型胶原的相互作用导致异常的PP 2A/HDAC 4轴，其抑制miR-29，导致I型胶原表达的病理性增加。
Idiopathic pulmonary fibrosis (IPF) is characterized by the relentless expansion of fibroblasts depositing type I collagen within the alveolar wall and obliterating the alveolar airspace. MicroRNA (miR)-29 is a potent regulator of collagen expression. In IPF, miR-29 levels are low, whereas type I collagen expression is high. However, the mechanism for suppression of miR-29 and increased type I collagen expression in IPF remains unclear. Here we show that when IPF fibroblasts are seeded on polymerized type I collagen, miR-29c levels are suppressed and type I collagen expression is high. In contrast, miR-29c is high and type I collagen expression is low in control fibroblasts. We demonstrate that the mechanism for suppression of miR-29 during IPF fibroblast interaction with polymerized collagen involves inappropriately low protein phosphatase (PP) 2A function, leading to histone deacetylase (HDA) C4 phosphorylation and decreased nuclear translocation of HDAC4. We demonstrate that overexpression of HDAC4 in IPF fibroblasts restored miR-29c levels and decreased type I collagen expression, whereas knocking down HDAC4 in control fibroblasts suppressed miR-29c levels and increased type I collagen expression. Our data indicate that IPF fibroblast interaction with polymerized type I collagen results in an aberrant PP2A/HDAC4 axis, which suppresses miR-29, causing a pathologic increase in type I collagen expression.