Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China; Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden.
Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden.
Vascul Pharmacol. 2014 Jan;60(1):42-8. doi: 10.1016/j.vph.2013.11.004. Epub 2013 Dec 5.
Vasoconstrictive endothelin type B (ET(B)) receptors promote vasospasm and ischemic cerebro- and cardiovascular diseases. The present study was designed to examine if low density lipoprotein (LDL) induces upregulation of vasoconstrictive ET(B) receptor expression and if extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signal pathways are involved in this process. Rat mesenteric artery segments were organ cultured in the presence and absence of LDL with or without inhibitors for MAPK kinase 1 and 2 (MEK1/2), p38 and transcription. The upregulation of vasoconstrictive ET(B) receptor expression was studied using a sensitive myograph, real-time PCR and Western blot. LDL (11, 22 and 44 mg protein/L) concentration-dependently induced upregulation of vasoconstrictive ETB receptor expression with increase in the receptor-mediated vasoconstriction, elevated levels of the ET(B) receptor mRNA and protein expressions, and activation of ERK1/2 and p38 MAPK. Blockage of ERK1/2 and p38 MAPK signal pathways using MEK1/2 inhibitors (PD98059 and U0126) or p38 inhibitors (SB203580 and SB239063) significantly abolished the LDL-induced upregulation of vasoconstrictive ET(B) receptor expression. Actinomycin D (general transcriptional inhibitor) almost completely inhibited the LDL effects. In conclusion, LDL induces upregulation of vasoconstrictive ET(B) receptor expression through activation of ERK1/2 and p38 MAPK signal pathway-dependent transcriptional mechanisms.
血管收缩性内皮素 B (ET(B)) 受体促进血管痉挛和缺血性脑心和心血管疾病。本研究旨在研究低密度脂蛋白 (LDL) 是否诱导血管收缩性 ET(B) 受体表达上调，以及细胞外信号调节激酶 1 和 2 (ERK1/2) 和 p38 丝裂原激活蛋白激酶 (MAPK) 信号通路是否参与这一过程。在存在和不存在 LDL 的情况下，将大鼠肠系膜动脉段在器官培养物中培养，同时存在或不存在 MAPK 激酶 1 和 2 (MEK1/2)、p38 和转录抑制剂。使用灵敏的肌动描记器、实时 PCR 和 Western blot 研究血管收缩性 ET(B) 受体表达的上调。LDL (11、22 和 44 mg 蛋白/L) 浓度依赖性地诱导血管收缩性 ETB 受体表达上调，导致受体介导的血管收缩增加、ET(B) 受体 mRNA 和蛋白表达水平升高以及 ERK1/2 和 p38 MAPK 的激活。使用 MEK1/2 抑制剂 (PD98059 和 U0126) 或 p38 抑制剂 (SB203580 和 SB239063) 阻断 ERK1/2 和 p38 MAPK 信号通路，显著抑制了 LDL 诱导的血管收缩性 ET(B) 受体表达上调。放线菌素 D(一般转录抑制剂)几乎完全抑制了 LDL 的作用。总之，LDL 通过激活 ERK1/2 和 p38 MAPK 信号通路依赖性转录机制诱导血管收缩性 ET(B) 受体表达上调。
