Institute of Neuroscience, Soochow University, Suzhou 215123, China.
Cell Signal. 2013 Nov;25(11):2255-62. doi: 10.1016/j.cellsig.2013.07.010. Epub 2013 Jul 18.
Hydrogen sulfide (H2S), mainly produced by cystathionine γ-lyase (CSE) in vascular system, emerges as a novel gasotransmitter exerting anti-inflammatory and anti-atherosclerotic effects. Alterations of CSE/H2S pathway may thus be involved in atherosclerosis pathogenesis. However, the underlying mechanisms are poorly understood. The present study showed that the levels of CSE mRNA and protein expression, as well as H2S production were decreased in ox-LDL-treated macrophage. CSE overexpression reduced the ox-LDL-stimulated tumor necrosis factor-α (TNF-α) generation in Raw264.7 and primary macrophage while CSE knockdown enhanced it. Exogenous supplementation of H2S with NaHS and Na2S also decreased the production of TNF-α and intercellular adhesion molecule-1 (ICAM-1) in ox-LDL-stimulated macrophage, and alleviated the adhesion of macrophage to endothelial monolayer. Cysteine, a CSE preferential substrate for H2S biosynthesis, produced similar effects on the pro-inflammatory cytokine generation, which were reversed by CSE inhibitors PAG and BCA, respectively. Moreover, NaHS and Na2S attenuated the phosphorylation and degradation of IκBα and p65 nuclear translocation, as well as JNK activation caused by ox-LDL. The JNK inhibitor suppressed the NF-κB transcription activity in ox-LDL-treated cells. Furthermore, inhibitors of NF-κB (PDTC), ERK (U0126 and PD98059) and JNK (SP600125) partially blocked the suppression by ox-LDL on the CSE mRNA levels. Taken together, the findings demonstrate that ox-LDL may down-regulate the CSE/H2S pathway, which plays an anti-inflammatory role in ox-LDL-stimulated macrophage by suppressing JNK/NF-κB signaling. The study reveals new therapeutic strategies for atherosclerosis, based on modulating CSE/H2S pathway.
硫化氢（H2S）主要由血管系统中的胱硫醚γ-裂解酶（CSE）产生，作为一种新型的气体递质发挥抗炎和抗动脉粥样硬化作用。因此，CSE/H2S 途径的改变可能与动脉粥样硬化的发病机制有关。然而，其潜在机制尚不清楚。本研究表明，在 ox-LDL 处理的巨噬细胞中，CSE mRNA 和蛋白表达水平以及 H2S 的产生均降低。CSE 的过表达降低了 ox-LDL 刺激的 Raw264.7 和原代巨噬细胞中肿瘤坏死因子-α（TNF-α）的产生，而 CSE 的敲低则增强了其产生。用 NaHS 和 Na2S 作为外源性 H2S 补充剂也降低了 ox-LDL 刺激的巨噬细胞中 TNF-α和细胞间黏附分子-1（ICAM-1）的产生，并减轻了巨噬细胞与内皮单层的黏附。CSE 合成 H2S 的优先底物半胱氨酸对促炎细胞因子的产生也产生了类似的作用，而 CSE 抑制剂 PAG 和 BCA 则分别逆转了这些作用。此外，NaHS 和 Na2S 减弱了 ox-LDL 引起的 IκBα磷酸化和降解以及 p65 核易位和 JNK 的激活。JNK 抑制剂抑制了 ox-LDL 处理细胞中的 NF-κB 转录活性。此外，NF-κB（PDTC）、ERK（U0126 和 PD98059）和 JNK（SP600125）抑制剂部分阻断了 ox-LDL 对 CSE mRNA 水平的抑制作用。总之，这些发现表明，ox-LDL 可能下调 CSE/H2S 途径，通过抑制 JNK/NF-κB 信号通路，在 ox-LDL 刺激的巨噬细胞中发挥抗炎作用。该研究为基于调节 CSE/H2S 途径的动脉粥样硬化提供了新的治疗策略。
