αvβ3-Integrin antagonists inhibit thrombin- induced proliferation and focal adhesion formation in smooth muscle cells
αvβ3-Integrin antagonists inhibit thrombin- induced proliferation and focal adhesion formation in smooth muscle cells
复制标题
DOI：
10.1152/ajpcell.00475.2002
复制
发表时间：
2003-11-01
影响因子：
5.5
通讯作者：
Stouffer, GA
中科院分区：
文献类型：
--
作者：
Sajid, M;Zhao, R;Stouffer, GA
在八种不同的动物模型中，α（v）β（3）-整合素拮抗剂减少血管损伤后的新生内膜形成。由于α-凝血酶促进新生内膜形成，我们检验了α（v）β（3）-整合素影响α-凝血酶诱导的信号传导的假设。培养的大鼠主动脉平滑肌细胞（RASMC）表达α（v）β（3）-整合素，如免疫荧光显微镜和荧光激活细胞分选分析所示。抗β 3整合素单克隆抗体F11和环RGD肽可部分抑制对α-凝血酶的反应。免疫荧光显微镜显示，α-凝血酶刺激局灶性粘连形成的快速增加，如粘着斑染色所示，这种作用部分被α（v）β（3）拮抗剂抑制。β（3）-整合素染色在静止的RASMC中是弥漫性的，并且在凝血酶处理后在局灶性粘连部位不集中。α-凝血酶引起c-Jun NH 2-末端激酶-1（JNK 1）活化和粘着斑激酶（FAK）酪氨酸磷酸化的时间依赖性增加。α（v）β（3）-整联蛋白拮抗剂部分抑制JNK 1活性的增加，但对FAK磷酸化没有影响。在从β 3整合素缺陷小鼠分离的SMC中，粘着斑的形成受到凝血酶的影响，但没有受到1-磷酸鞘氨醇（一种Rho的有效激活剂）的影响。总之，α（v）β（3）-整合素在α-凝血酶诱导的RASMC增殖和粘着斑形成中起重要作用。
alpha(v)beta(3)-Integrin antagonists reduced neointimal formation following vascular injury in eight different animal models. Because alpha-thrombin contributes to neointimal formation, we examined the hypothesis that alpha(v)beta(3)-integrins influence alpha-thrombin-induced signaling. Cultured rat aortic smooth muscle cells (RASMC) expressed alpha(v)beta(3)-integrins as demonstrated by immunofluorescence microscopy and fluorescence-activated cell sorting analysis. Proliferative responses to alpha-thrombin were partially inhibited by anti-beta(3)-integrin monoclonal antibody F11 and by cyclic RGD peptides. Immunofluorescence microscopy showed that alpha-thrombin stimulated a rapid increase in the formation of focal adhesions as identified by vinculin staining and that this effect was partially inhibited by alpha(v)beta(3) antagonists. beta(3)-Integrin staining was diffuse in quiescent RASMC and did not concentrate at sites of focal adhesions following thrombin treatment. alpha-Thrombin elicited a time-dependent increase in activation of c-Jun NH2-terminal kinase-1 (JNK1) and in tyrosine phosphorylation of focal adhesion kinase (FAK). alpha(v)beta(3)-Integrin antagonists partially inhibited increases in JNK1 activity but had no effect on FAK phosphorylation. In SMC isolated from beta(3)-integrin-deficient mice, focal adhesion formation was impaired in response to thrombin but not sphingosine-1-phosphate, a potent activator of Rho. In summary, alpha(v)beta(3)-integrins play an important role in alpha-thrombin-induced proliferation and focal adhesion formation in RASMC.