Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Biochem Biophys Res Commun. 2012 Jan 6;417(1):346-51. doi: 10.1016/j.bbrc.2011.11.113. Epub 2011 Dec 1.
It is well established that 4-hydroxynonenal (HNE) plays a major role in oxidative stress-induced signaling and the toxicity of oxidants. Surprisingly our recent studies also demonstrate that low levels of HNE generated during oxidative stress promote cell survival mechanisms and proliferation. Since the expression and secretion of VEGF is known to be affected by Oxidative stress, during present studies, we have examined dose dependent effect of HNE on VEGF expression and secretion in a model of retinal pigment epithelial (RPE) cells in culture. Results of these studies showed that while inclusion of 0.1 μM HNE in the medium caused increased secretion of VEGF, its secretion and expression was significantly suppressed in the presence of >5 μM HNE in the media. These concentration dependent hormetic effects of HNE on VEGF secretion could be blocked by the over expression of GSTA4-4 indicating that these effects were specifically attributed to HNE and regulated by GSTA4-4. VEGF secreted into the media showed angiogenic properties as indicated by increased migration and tube formation of HUVEC in matrigel when grown in media from RPE cells treated with 1 μM HNE. The corresponding media from GSTA4-4 over expressing RPE cells had no effect on migration and tube formation of HUVEC in matrigel. These results are consistent with earlier studies showing that at low concentrations, HNE promotes proliferative mechanisms and suggest that HNE induces VEGF secretion from RPE cells that acts in a paracrine fashion to induce angiogenic signaling mechanism in the endothelial cells. These findings may suggest a role of HNE and GSTA4-4 in oxidative stress induced proliferative retinopathies.
众所周知，4-羟基壬烯醛（HNE）在氧化应激诱导的信号转导和氧化剂的毒性中起主要作用。令人惊讶的是，我们最近的研究还表明，氧化应激过程中产生的低水平 HNE 促进细胞存活机制和增殖。由于已知血管内皮生长因子（VEGF）的表达和分泌受氧化应激影响，因此在目前的研究中，我们检查了 HNE 在培养的视网膜色素上皮（RPE）细胞模型中对 VEGF 表达和分泌的剂量依赖性影响。这些研究的结果表明，虽然培养基中包含 0.1 μM HNE 会导致 VEGF 分泌增加，但当培养基中存在>5 μM HNE 时，其分泌和表达显著受到抑制。HNE 对 VEGF 分泌的这种浓度依赖性兴奋效应可以被 GST A4-4 的过表达所阻断，表明这些效应是专门归因于 HNE 并由 GST A4-4 调节的。分泌到培养基中的 VEGF 表现出血管生成特性，这表明当在培养基中培养时，HUVEC 的迁移和管形成增加，所述培养基来自用 1 μM HNE 处理的 RPE 细胞。来自 GST A4-4 过表达的 RPE 细胞的相应培养基对 HUVEC 在 Matrigel 中的迁移和管形成没有影响。这些结果与早期研究一致，表明在低浓度下，HNE 促进增殖机制，并表明 HNE 诱导 RPE 细胞分泌 VEGF，该 VEGF 以旁分泌方式作用于内皮细胞中的血管生成信号机制。这些发现可能表明 HNE 和 GST A4-4 在氧化应激诱导的增殖性视网膜病变中的作用。
