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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/H627    most recent 00444.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Manso, A. M. Articles by Ross, R. S. Search for Related Content PubMed PubMed Citation Articles by Manso, A. M. Articles by Ross, R. S.

Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration

¹Department of Medicine, University of California-San Diego School of Medicine, La Jolla, California; ²Veterans Administration Healthcare, San Diego, California; ³Cardiology Division, Yonsei University College of Medicine, Seoul, Korea; ⁴Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; ⁵Department of Ophthalmology, University of California, San Francisco, California

Submitted 28 April 2008 ; accepted in final form 5 January 2009

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.

extracellular matrix; cytoskeleton; fibroblast

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