ATVB：血管重构发生机制研究的新进展
最近，由山东大学张运院士领导的课题组在血管重构发生机制和基因干预研究方面取得了新的突破性成果。4月1日，美国心脏协会（American Heart Association）主办的国际权威心血管病杂志《动脉硬化、血栓形成与血管生物学》（Arteriosclerosis,Thrombosis,and Vascular Biology）全文发表了该项研究成果，并在杂志封面刊登了该文的图片。
血管重构是近年来国际心血管病研究的前沿领域。近年研究发现，血管外膜的成纤维细胞（AF）在血管重构的发生和发展中起着重要作用，但AF增殖的分子机制尚不清楚。本研究应用先进的分子生物学技术，在国际上首次证明转换生长因子TGF-β1介导的Smad，整联蛋白和MAPK信号转导通路间的交互对话是AF增殖的主要分子机制。整联蛋白是影响AF生物活性的主要信号转导通路，而整联蛋白β1是介导此通路的主要分子亚型。
同时，新研究在国际上首次应用特异性生长抑制同源基因（Gax）在转录水平对AF功能进行干预研究，证实Gax基因能够有效整合和负性调控AF的生物学活性。该项研究成果不仅有助于阐明动脉粥样硬化和血管介入治疗后再狭窄等血管重构病变的发病机制，而且为干预血管重构提供了新的治疗靶点，从而具有重要的临床应用前景。刘平、张澄和冯进波等为该文的共同第一作者，张运院士为该文的通讯作者。编辑部在给作者的信中高度评价了这一工作，认为这是一项具有原创性的重要研究。（来源：山东大学 高飞）
生物谷推荐原始出处：
（Arteriosclerosis,Thrombosis,and Vascular Biology），2008,28(4):725-731，Ping Liu; Yun Zhang
Cross Talk Among Smad, MAPK, and Integrin Signaling Pathways Enhances Adventitial Fibroblast Functions Activated by Transforming Growth Factor–β1 and Inhibited by Gax
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@sdu.edu.cn
Abstract
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.
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