Liu Jean-Dean, Tsai Shu-Huei, Lin Shyr-Yi, Ho Yuan-Soon, Hung Ling-Fang, Pan Shiann, Ho Feng-Ming, Lin Chun-Mao, Liang Yu-Chih
College of Medicine, Taipei Medical University, Taipei, Taiwan.
Life Sci. 2004 Mar 26;74(19):2451-63. doi: 10.1016/j.lfs.2003.10.007.
Heme oxygenase-1 (HO-1) is induced as a beneficial and adaptive response in cells and tissues exposed to oxidative stress. Herein we examined how various eicosanoids affect the induction of HO-1, and the possible mechanism underlying 15-deoxy-Delta(12,14)- prostaglandin J(2) (15d-PGJ(2))-induced HO-1 expression. PGH(2), PGD(2) and its metabolites of the PGJ(2) series, and PGA(1) markedly induced the protein expression of HO-1. Arachidonic acid (AA), docosahexaenoic acid (DHA), PGE(2), PGF(2 alpha), and thromboxane B(2) (TXB(2)) were shown to have no effect on the induction of HO-1. 15d-PGJ(2) was the most potent activator achieving significance at 5 microM. Although 15d-PGJ(2) significantly activated the MAPKs of JNK and ERK, the activation of JNK and ERK did not contribute to the induction of HO-1 as determined using transfection of dominant-negative plasmids and MAPKs inhibitors. Additional experiment indicated that 15d-PGJ(2) induced HO-1 expression through peroxisome proliferator-activated receptor (PPAR)-independent pathway. 15d-PGJ(2) significantly decreased the intracellular level of reduced glutathione; and the thiol antioxidant, N-acetyl-L-cysteine (NAC), and the thiol-reducing agent, dithiothreitol (DTT), inhibited the induction of HO-1 by 15d-PGJ(2). Finally, NAC and DTT exhibited significant inhibition of HO-1 mRNA and HO-1 promoter reporter activity induced by 15d-PGJ(2). These results suggest that thiol antioxidant and reducing agents attenuate the expression of HO-1 induced by 15d-PGJ(2), and that the cellular thiol-disulfide redox status may be linked to HO-1 activation.
血红素加氧酶-1（HO-1）在暴露于氧化应激的细胞和组织中作为一种有益的适应性反应被诱导产生。在此，我们研究了各种类花生酸如何影响HO-1的诱导，以及15-脱氧-Δ¹²,¹⁴-前列腺素J₂（15d-PGJ₂）诱导HO-1表达的潜在机制。前列腺素H₂（PGH₂）、前列腺素D₂（PGD₂）及其PGJ₂系列代谢产物以及前列腺素A₁（PGA₁）显著诱导HO-1的蛋白表达。花生四烯酸（AA）、二十二碳六烯酸（DHA）、前列腺素E₂（PGE₂）、前列腺素F₂α（PGF₂α）和血栓素B₂（TXB₂）对HO-1的诱导无影响。15d-PGJ₂是最有效的激活剂，在5微摩尔时具有显著作用。虽然15d-PGJ₂显著激活了JNK和ERK的丝裂原活化蛋白激酶（MAPK），但通过转染显性负性质粒和MAPK抑制剂确定，JNK和ERK的激活对HO-1的诱导没有贡献。额外的实验表明，15d-PGJ₂通过不依赖过氧化物酶体增殖物激活受体（PPAR）的途径诱导HO-1表达。15d-PGJ₂显著降低了细胞内还原型谷胱甘肽的水平；硫醇抗氧化剂N-乙酰-L-半胱氨酸（NAC）和硫醇还原剂二硫苏糖醇（DTT）抑制了15d-PGJ₂对HO-1的诱导。最后，NAC和DTT对15d-PGJ₂诱导的HO-1 mRNA和HO-1启动子报告基因活性表现出显著抑制作用。这些结果表明硫醇抗氧化剂和还原剂减弱了15d-PGJ₂诱导的HO-1表达，并且细胞硫醇-二硫键氧化还原状态可能与HO-1激活有关。
