Low-affinity thromboxane receptor mediates proliferation in cultured vascular smooth muscle cells of rats

被引:8
作者
Ko, FN
机构
[1] Pharmacological Institute, College of Medicine, National Taiwan University, Taipei
[2] Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, No. 1, Jen-Ai Rd
关键词
thromboxane receptor; mitogen-activated protein kinase; vascular smooth muscle cell; proliferation; protein kinase C;
D O I
10.1161/01.ATV.17.7.1274
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We examined the binding properties and mitogenic effects of U46619, using cultured vascular smooth muscle cells (VSMCs), bq ligand-binding assay, measuring [H-3]thymidine and [H-3]leucine incorporation, checking with flow cytometry, and counting the cell number. The U46619-activated mitogenic signal-transduction pathway was assessed by measuring formation of inositol monophosphate (IF); [Ca2+](i); mitogen-activated protein kinase (MAPK), MAPK kinase (MAPKK), and p74raf-1 activities: and i;m-bound Ras. [H-3]U46619 bound to cultured VSMCs from Wistar-Kyoto (WKY) rats at a single class of site (K-d; 15.5+/-2.6 mmol/L). However, it bound to VSMCs from spontaneously hypertensive rats (SHRs) at two classes of sites (K-d: 2.3+/-0.6 nmol/L and 1.4+/-0.5 mu mol/L). U46619 increased DNA and protein synthesis, cell number, IP formation, [Ca2+](i), and MAPK and MAPKK activities, with EC50 values close to its K-d value for the low-affinity binding site in VSMCs from SHR. Prostaglandin (PG) E-2 and PGF(2a) showed little of such mitogenic effects. All these effects of U46619 were inhibited by SQ29548, staurosporine, or pretreatment of VSMCs with phorbol 12-myristate 13-acetate for 24 hours. However, U46619 stimulation did not lead to a significant increase in the Ras-GTP complex or p74raf-1 activity. In conclusion, the mitogenic effect of U46619 appears to be mediated via the activation of low-affinity thromboxane binding sites that trigger phosphoinositide hydrolysis and activate the MAPK pathway, leading to DNA synthesis and cell proliferation.
引用
收藏
页码:1274 / 1282
页数:9
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