Biological Sciences, Allergan, Inc., Irvine, California 92612, USA.
Invest Ophthalmol Vis Sci. 2011 Feb 22;52(2):890-903. doi: 10.1167/iovs.10-5715.
To investigate the role of the peroxisome proliferator-activated receptor (PPAR)-γ in modulating retinal pigmented epithelium (RPE) responses to oxidative stress.
ARPE-19 cells were treated with the oxidant, t-butylhydroperoxide (tBH) to induce apoptosis. Cells pretreated with synthetic PPARγ agonists of the antidiabetic thiazolidinediones class before tBH challenge were assessed for viability and, by microarray analysis, for effects on gene expression.
Treatment of ARPE-19 cells with tBH resulted in a loss of viability and global changes in the pattern of gene expression. PPARγ ligands were found to have differential modulatory effects on tBH-induced apoptosis of RPE cells. Whereas rosiglitazone and pioglitazone potentiated cell death, troglitazone acted as a potent cytoprotective agent. Downregulation of PPARγ expression by an siRNA resulted in enhanced cell death in response to tBH treatment and blocked the cytoprotective effect of troglitazone consistent with a role of PPARγ in mediating this response. Microarray analysis revealed that while rosiglitazone and pioglitazone had little effect on gene changes induced by tBH treatment, troglitazone dramatically reduced the number of changes caused by oxidative stress. A unique subset of genes that were deregulated by tBH and selectively normalized by troglitazone were identified.
These findings demonstrate that PPARγ agonists can have differential effects on RPE survival in response to oxidative stress. Oxidative stress leads to deregulation of a large set of genes in ARPE-19 cells. A specific subset of these genes can be selectively modulated by troglitazone and represent potential novel targets for cytoprotective therapies.
研究过氧化物酶体增殖物激活受体（PPAR）-γ在调节视网膜色素上皮（RPE）对氧化应激的反应中的作用。
用氧化剂 t-丁基过氧化氢（tBH）处理 ARPE-19 细胞以诱导细胞凋亡。用噻唑烷二酮类抗糖尿病的合成 PPARγ激动剂预处理 tBH 攻击前的细胞，以评估细胞活力，并通过微阵列分析评估对基因表达的影响。
用 tBH 处理 ARPE-19 细胞导致细胞活力丧失和基因表达模式的全局变化。发现 PPARγ 配体对 RPE 细胞 tBH 诱导的细胞凋亡具有不同的调节作用。虽然罗格列酮和吡格列酮增强细胞死亡，曲格列酮则表现出有效的细胞保护作用。用 siRNA 下调 PPARγ 表达导致对 tBH 处理的细胞死亡增加，并阻断了曲格列酮的细胞保护作用，表明 PPARγ 在介导这种反应中起作用。微阵列分析显示，虽然罗格列酮和吡格列酮对 tBH 处理诱导的基因变化影响不大，但曲格列酮显著减少了由氧化应激引起的变化数量。确定了一组由 tBH 调节且被曲格列酮选择性归一化的独特基因子集。
这些发现表明，PPARγ 激动剂对 RPE 在氧化应激下的存活可能有不同的影响。氧化应激导致 ARPE-19 细胞中一组大量基因失调。这些基因的一个特定子集可以被曲格列酮特异性调节，代表潜在的新的细胞保护治疗靶点。
