Kwok Ching Fai, Juan Chi-Chang, Ho Low-Tone
Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Am J Physiol Endocrinol Metab. 2007 Feb;292(2):E648-52. doi: 10.1152/ajpendo.00084.2006. Epub 2006 Sep 19.
Recent studies have shown that CD36 plays important roles as a major scavenger receptor for oxidized low-density lipoproteins and as a crucial transporter for long-chain fatty acids. CD36 deficiency might be associated with insulin resistance and abnormal dynamics of long-chain fatty acids. Endothelin-1 (ET-1), which is synthesized and secreted by vascular endothelial cells, is the most potent endogenous vasoconstrictor known and also stimulates the proliferation of vascular smooth muscle cells (VSMCs) and thus is believed to play an important role in the development of various circulatory disorders, including hypertension and atherosclerosis. The aim of the present study was to investigate the regulatory effect of ET-1 on CD36 expression in cultured VSMCs. VSMCs were treated for different times (0-24 h) with a fixed concentration (100 nM) of ET-1 or with different concentrations (0-100 nM) for a fixed time (24 h); then CD36 expression was determined using Western blots. CD36 expression was significantly decreased by ET in a time- and dose-dependent manner. This inhibitory effect was prevented by the ET(A) receptor antagonist BQ-610 (10 microM) but not the ET(B) receptor antagonist BQ-788 (10 microM). To further explore the underlying mechanisms of ET-1 action, we examined the involvement of the tyrosine kinase-mediated and MAPK-mediated pathways. The inhibitory effect of ET-1 on CD36 protein expression was blocked by inhibition of tyrosine kinase activation by use of genistein (100 microM) and by the ERK inhibitor PD-98059 (75 microM) but not by the p38 MAPK inhibitor SB-203580 (20 microM). In conclusion, we have demonstrated that ET-1, acting via the ET(A) receptor, suppresses CD36 protein expression in VSMCs by activation of the tyrosine kinase and ERK pathways.
最近的研究表明，CD36作为氧化型低密度脂蛋白的主要清道夫受体以及长链脂肪酸的关键转运体发挥着重要作用。CD36缺乏可能与胰岛素抵抗及长链脂肪酸的异常动态变化有关。内皮素-1（ET-1）由血管内皮细胞合成并分泌，是已知最强效的内源性血管收缩剂，还能刺激血管平滑肌细胞（VSMC）增殖，因此被认为在包括高血压和动脉粥样硬化在内的各种循环系统疾病的发生发展中起重要作用。本研究的目的是探讨ET-1对培养的VSMC中CD36表达的调节作用。用固定浓度（100 nM）的ET-1处理VSMC不同时间（0 - 24小时），或用不同浓度（0 - 100 nM）处理固定时间（24小时）；然后使用蛋白质免疫印迹法测定CD36表达。ET以时间和剂量依赖性方式显著降低CD36表达。ET(A)受体拮抗剂BQ-610（10 microM）可阻止这种抑制作用，但ET(B)受体拮抗剂BQ-788（10 microM）则不能。为了进一步探究ET-1作用的潜在机制，我们研究了酪氨酸激酶介导的途径和丝裂原活化蛋白激酶（MAPK）介导的途径。使用染料木黄酮（100 microM）抑制酪氨酸激酶激活以及使用ERK抑制剂PD-98059（75 microM）可阻断ET-1对CD36蛋白表达的抑制作用，但p38 MAPK抑制剂SB-203580（20 microM）则不能。总之，我们证明了ET-1通过ET(A)受体，通过激活酪氨酸激酶和ERK途径抑制VSMC中CD36蛋白的表达。
