Transforming growth factor-β1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase
Transforming growth factor-β1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase
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DOI：
10.1067/msy.2002.125304
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发表时间：
2002-08-01
期刊：
影响因子：
3.8
通讯作者：
Mignatti, P
中科院分区：
文献类型：
--
作者：
Hyman, KM;Seghezzi, G;Mignatti, P
背景资料。血管内皮细胞凋亡是动脉粥样硬化和内膜增生的中心环节。转化生长因子-β1通过不明机制诱导内皮细胞凋亡(S)。虽然转化生长因子-β1通过Smad蛋白传递信号，但在某些非内皮细胞类型中，它也激活丝裂原活化蛋白激酶(MAPK)(细胞外信号调节激酶、c-jun氨基末端激酶和p38MAPK[p.38(MAPK)])。P38(MAPK)在多种细胞类型中传递凋亡信号。我们假设转化生长因子-β1通过激活p38(MAPK)激活内皮细胞MAPKs并诱导其凋亡。人脐静脉或牛毛细血管内皮细胞与转化生长因子-β1共同孵育0.5~12h。用磷酸化的细胞外信号调节激酶1/2、p38(MAPK)或c-jun氨基末端激酶1/2的抗体进行Western blotting检测MAPK的活性。为了研究细胞的凋亡，用含或不含MAPK抑制剂的转化生长因子-β1孵育6h的细胞提取液进行Western blotting分析聚(ADP-Ribose)聚合酶降解情况。转化生长因子-β1诱导p38(MAPK)、细胞外信号调节蛋白1/2和c-jun氨基末端蛋白激酶1/2活化，促进细胞凋亡。抑制p38MAPK可显著减少转化生长因子-β1诱导的细胞凋亡。相反，对其他信号通路的抑制无效。转化生长因子-β1通过激活p38(MAPK)诱导内皮细胞凋亡。由于转化生长因子-β1在血管重塑过程中表达上调，p38(MAPK)在这一过程中是一个潜在的防止内皮细胞凋亡的靶点。
Background. Vascular endothelial cell apoptosis is central in atherosclerosis and intimal hyperplasia. Transforming growth factor (TGF)-beta1 induces endothelial cell apoptosis through unidentified mechanism(s). Although TGF-beta1 signals through the Smad proteins, in some nonendothelial cell types it also activates the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK [p.38(MAPK)]). p38(MAPK) relays apoptotic signals in several cell types. We hypothesized that TGF-beta1 activates endothelial cell MAPKs and induces apoptosis through p38(MAPK) activation.Methods. Human umbilical vein or bovine capillary endothelial cells were incubated with TGF-beta1 for 0.5 to 12 hours. MAPK activation was characterized by Western blotting with antibodies to phosphorylated extracellular signal-regulated kinase 1/2, p38(MAPK), or c-Jun N-terminal kinases 1/2. To study apoptosis, extracts of cells incubated with TGF-beta1 for 6 hours with or without MAPK inhibitors were characterized by Western blotting analysis of poly (ADP-Ribose) polymerase degradation.Results. TGF-beta1 induced p38(MAPK), extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase 1/2 activation and increased apoptosis. Inhibition of p38MAPK significantly reduced TGF-beta1-induced apoptosis. In contrast, inhibition of other signaling pathways was ineffective.Conclusions. TGF-beta1 induces endothelial cell apoptosis through p38(MAPK) activation. Because TGF-beta1 is upregulated in vascular remodeling, p38(MAPK) is a potential target to prevent endothelial cell apoptosis during this process.