Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration
Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration
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DOI：
10.1152/ajpheart.00444.2008
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发表时间：
2009-03-01
影响因子：
4.8
通讯作者：
Ross, Robert S.
中科院分区：
文献类型：
--
作者：
Manso, Ana Maria;Kang, Seok-Min;Ross, Robert S.
MANSO AM，康SM，Plotnikov SV，Thievessen I，oh J，Beges He，Ross RS.心脏成纤维细胞需要粘着斑激酶才能正常增殖和迁移。Am J Physiol心脏圈Physiol 296：H627-H638,2009。2009年1月9日首次出版；doi：10.1152/ajpheart.00444.2008。-心脏成纤维细胞(CFs)的迁移和增殖在心肌重塑过程中发挥着重要作用。虽然已经确定了许多调节CFs生长和迁移的因素，但对这些过程中涉及的信号机制知之甚少。在这里，我们利用Cre-loxP技术获得了粘着斑激酶(FAK)缺乏的成年小鼠CFs，并研究了FAK在调节这些细胞的黏附、增殖和迁移中的作用。用Ad/Cre病毒处理FAK(FLOX/FLOX)CFs后，细胞内FAK蛋白水平下降了70%以上。FAK缺乏的CFs在局部粘连、细胞形态或纽蛋白、Talin或Paxlin的蛋白表达水平上没有变化；富含Pro的酪氨酸激酶2(PYK2)的表达和活性增加。下调CFs中FAK蛋白的表达可增加PDGF-BB诱导的细胞增殖，同时抑制PDGF-BB诱导的迁移。与纤维连接蛋白的粘附性没有改变。为了区分FAK和PYK2的功能，通过腺病毒介导的天然FAK抑制因子FAK相关非激酶(Frnk)的过表达来抑制FAK的功能。Ad/FRANK对PYK2表达无影响，可抑制PDGF-BB诱导的细胞迁移，但不改变PDGF-BB诱导的细胞增殖。FAK缺乏仅对p38和JNK MAPK的PDGF-BB激活有轻微影响，而ERK反应与对照组相比无明显变化。这些结果表明，FAK在PDGF-BB诱导的成年小鼠CFs的迁移反应中是必需的，并表明FAK可能在许多心脏病理中发生的创伤修复反应中发挥重要作用。
Manso AM, Kang SM, Plotnikov SV, Thievessen I, Oh J, Beggs HE, Ross RS. Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration. Am J Physiol Heart Circ Physiol 296: H627-H638, 2009. First published January 9, 2009; doi:10.1152/ajpheart.00444.2008.-Migration and proliferation of cardiac fibroblasts (CFs) play an important role in the myocardial remodeling process. While many factors have been identified that regulate CF growth and migration, less is known about the signaling mechanisms involved in these processes. Here, we utilized Cre-LoxP technology to obtain focal adhesion kinase (FAK)-deficient adult mouse CFs and studied how FAK functioned in modulating cell adhesion, proliferation, and migration of these cells. Treatment of FAK(flox/flox) CFs with Ad/Cre virus caused over 70% reduction of FAK protein levels within a cell population. FAK-deficient CFs showed no changes in focal adhesions, cell morphology, or protein expression levels of vinculin, talin, or paxillin; proline-rich tyrosine kinase 2 (Pyk2) expression and activity were increased. Knockdown of FAK protein in CFs increased PDGF-BB-induced proliferation, while it reduced PDGF-BB-induced migration. Adhesion to fibronectin was not altered. To distinguish between the function of FAK and Pyk2, FAK function was inhibited via adenoviral-mediated overexpression of the natural FAK inhibitor FAK-related nonkinase (FRNK). Ad/FRNK had no effect on Pyk2 expression, inhibited the PDGF-BB-induced migration, but did not change the PDGF-BB-induced proliferation. FAK deficiency had only modest effects on increasing PDGF-BB activation of p38 and JNK MAPKs, with no alteration in the ERK response vs. control cells. These results demonstrate that FAK is required for the PDGF-BB-induced migratory response of adult mouse CFs and suggest that FAK could play an essential role in the wound-healing response that occurs in numerous cardiac pathologies.