This Article Full Text Full Text (PDF) Additional Materials All Versions of this Article: 28/4/725    most recent ATVBAHA.107.159889v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liu, P. Articles by Zhang, Y. Search for Related Content PubMed PubMed Citation Articles by Liu, P. Articles by Zhang, Y. Related Collections Cell signalling/signal transduction Gene expression Gene regulation Growth factors/cytokines Gene therapy Mechanism of atherosclerosis/growth factors Other Vascular biology Other Research

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:725.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Cross Talk Among Smad, MAPK, and Integrin Signaling Pathways Enhances Adventitial Fibroblast Functions Activated by Transforming Growth Factor–β1 and Inhibited by Gax

Ping Liu; Cheng Zhang; Jin Bo Feng; Yu Xia Zhao; Xu Ping Wang; Jian Min Yang; Ming Xiang Zhang; Xing Li Wang; Yun Zhang

From the Key Laboratory of Cardiovascular Remodeling and Function Research (P.L., C.Z., J.B.F., Y.X.Z., X.P.W., J.M.Y., M.X.Z., Y.Z.), Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, China; the Second Hospital of Shandong University (P.L.), Jinan, Shandong, China; and the Texas Heart Institute at St Luke’s Episcopal Hospital (X.L.W.), Division of Cardiothoracic Surgery, Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Tex.

Correspondence to Yun Zhang, MD, PhD, Shandong University Qilu Hospital, Jinan, No.107, Wen Hua Xi Road, Jinan, Shandong, 250012, P.R. China. E-mail zhangyun{at}sdu.edu.cn

Objective— We investigated whether Smad, mitogen-activated protein kinase (MAPK), and integrin signaling pathways cross-talk to enhance adventitial fibroblast (AF) bioactivity, which was activated by transforming growth factor (TGF)-β1 and inhibited by Gax.

Methods and Results— Cultured AFs were stimulated with Ad-Gax, TGF-β1, and siRNA-Gax. Assays for AFs viabilities demonstrated that TGF-β1 and siRNA-Gax enhanced AFs proliferative, migratory, and adherent abilities, whereas Gax counteracted TGF-β1–activated actions. Flow cytometry revealed that TGF-β1 and siRNA-Gax increased S phase cells; however, Gax decreased AFs in the S phase and increased those in the G0-G1 and apoptotic phases. RT-PCR, Western blotting, and immunocytochemistry showed that TGF-β1 and siRNA-Gax upregulated the expression of cytokines in Smad, MAPK, and integrin signaling pathways, and downregulated that of p15, p16, and p21. Conversely, Gax induced downregulation of these cytokines and upregulation of p15, p16, and p21. Thus, these signaling pathways cross-talk to enhance AF bioactivity; Gax effectively counteracts TGF-β1 effects, blocks the cross-talk of these pathways, inhibits AF functions, and increases AF apoptosis.

Conclusions— Our findings indicate that cross-talk among Smad, MAPK, and integrin signaling pathways may account mainly for the mechanism of AF functions. Gax is a promising therapeutic gene for dissecting the signaling pathways controlling AF bioactivities.

We investigated whether Smad, MAPK, and integrin signaling pathways cross-talk to enhance adventitial fibroblast (AF) bioactivity activated by TGF-β1. We found Gax counteracted TGF-β1 effects, blocked the cross-talk of these pathways, and inhibited AF functions. Thus, Gax is a promising therapeutic gene for dissecting the signaling pathways controlling AF bioactivities.

Key Words: adventitial fibroblast • signaling pathway • cell function • TGF-β1 • Gax