Angiotensin-II Mediates Nonmuscle Myosin II Activation and Expression and Contributes to Human Keloid Disease Progression
Angiotensin-II Mediates Nonmuscle Myosin II Activation and Expression and Contributes to Human Keloid Disease Progression
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DOI：
10.2119/molmed.2010.00265
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发表时间：
2011-11-01
影响因子：
5.7
通讯作者：
Levinson, Howard
中科院分区：
文献类型：
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作者：
Bond, Jennifer E.;Bergeron, Andrew;Levinson, Howard
成纤维细胞对成纤维肽的异常迁移在瘢痕疙瘩的发病中起重要作用。血管紧张素II （Ang II）是一种八肽激素，最近被认为是器官纤维化和皮肤修复的中介。Ang II促进细胞迁移，但其在瘢痕疙瘩成纤维细胞表型行为中的作用尚未研究。我们研究了瘢痕疙瘩成纤维细胞行为中的Ang II信号作为疾病的潜在机制。在存在Ang II和Ang II受体1 （AT(1)）、Ang II受体2 （AT(2)）或非肌肉肌球蛋白II （NMM II）拮抗剂的情况下，刺激原代人瘢痕疙瘩成纤维细胞迁移。瘢痕疙瘩及周围正常真皮免疫染色检测NMM IIA、NMM IIB、AT(2)和AT(1)表达。用Ang II刺激原代人瘢痕疙瘩成纤维细胞迁移，AT(1)拮抗剂EMD66684抑制其迁移，而AT(2)拮抗剂PD123319不抑制其迁移。通过添加特异性NMM II拮抗剂blebbistatin抑制促迁移运动蛋白NMM II，抑制Ang II刺激的迁移。AT(1)阻断可阻止Ang II对NMM II蛋白表达的刺激，而AT(2)拮抗剂则不能。免疫染色显示瘢痕疙瘩成纤维细胞中NMM IIA、NMM IIB和AT(1)的表达增加，而正常周围真皮中染色较少。瘢痕疙瘩和正常人真皮成纤维细胞未见AT(2)免疫染色。这些结果表明，Ang II介导瘢痕疙瘩成纤维细胞的迁移，并可能通过AT(1)激活和NMM II的上调介导其发病。(C) 2011范斯坦医学研究所，www.feinsteininstitute.org在线地址：http://www.molmed.org doi: 10.2119/molmed.2010.00265
Aberrant fibroblast migration in response to fibrogenic peptides plays a significant role in keloid pathogenesis. Angiotensin II (Ang II) is an octapeptide hormone recently implicated as a mediator of organ fibrosis and cutaneous repair. Ang II promotes cell migration but its role in keloid fibroblast phenotypic behavior has not been studied. We investigated Ang II signaling in keloid fibroblast behavior as a potential mechanism of disease. Primary human keloid fibroblasts were stimulated to migrate in the presence of Ang II and Ang II receptor 1 (AT(1)), Ang II receptor 2 (AT(2)) or nonmuscle myosin II (NMM II) antagonists. Keloid and the surrounding normal dermis were immunostained for NMM IIA, NMM IIB, AT(2) and AT(1) expression. Primary human keloid fibroblasts were stimulated to migrate with Ang II and the increased migration was inhibited by the AT(1) antagonist EMD66684, but not the AT(2) antagonist PD123319. Inhibition of the promigratory motor protein NMM II by addition of the specific NMM II antagonist blebbistatin inhibited Ang II-stimulated migration. Ang II stimulation of NMM II protein expression was prevented by AT(1) blockade but not by AT(2) antagonists. Immunostaining demonstrated increased NMM IIA, NMM IIB and AT(1) expression in keloid fibroblasts compared with scant staining in normal surrounding dermis. AT(2) immunostaining was absent in keloid and normal human dermal fibroblasts. These results indicate that Ang II mediates keloid fibroblast migration and possibly pathogenesis through AT(1) activation and up-regulation of NMM II. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2010.00265