Lee Eun Ji, Won Jun Pil, Lee Hyuk Gyoon, Kim Eunsu, Hur Jinwoo, Lee Won Jin, Hwang Jung Seok, Seo Han Geuk
College of Sang-Huh Life Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
Antioxidants (Basel). 2022 Jun 20;11(6):1207. doi: 10.3390/antiox11061207.
Emerging evidence shows that peroxisome proliferator-activated receptor delta (PPARδ) plays a pivotal role in cellular aging. However, its function in retinal disease processes such as hyperglycemia-associated diabetic retinopathy is unclear. Here, we demonstrate that PPARδ inhibits premature senescence of retinal pigment epithelial (RPE) cells induced by high glucose (HG) through SIRT1 upregulation. A specific ligand GW501516-activation of PPARδ suppressed premature senescence and production of reactive oxygen species induced by HG in ARPE-19 cells, a spontaneously arising human RPE cell line. These effects were accompanied by the regulation of the premature senescence-associated genes , , and . Furthermore, GW501516-activated PPARδ almost completely abolished the effects of HG treatment on the formation of phosphorylated H2A histone family member X (γ-H2A.X) foci, a molecular marker of aging. These inhibitory effects of GW501516 were significantly reversed in ARPE-19 cells stably expressing small hairpin RNA targeting PPARδ. Notably, GW501516 significantly increased the mRNA and protein levels of SIRT1, indicating that GW501516-activated PPARδ exerted its beneficial effects through SIRT1. In addition, GW501516 restored HG-suppressed SIRT1 expression, corroborating the role of SIRT1 in the anti-senescence function of PPARδ. The effects of PPARδ on HG-induced premature senescence and the expression of the senescence-associated genes p53, p21, and SMP-30 were mimicked by the SIRT1 activator resveratrol, but blocked by the SIRT1 inhibitor sirtinol. Collectively, these results indicate that GW501516-activated PPARδ inhibits HG-triggered premature senescence of RPE cells by modulating SIRT1 signaling.
新出现的证据表明，过氧化物酶体增殖物激活受体δ（PPARδ）在细胞衰老中起关键作用。然而，其在视网膜疾病过程（如高血糖相关的糖尿病视网膜病变）中的功能尚不清楚。在此，我们证明PPARδ通过上调SIRT1抑制高糖（HG）诱导的视网膜色素上皮（RPE）细胞过早衰老。PPARδ的特异性配体GW501516激活可抑制HG诱导的ARPE-19细胞（一种自发产生的人RPE细胞系）过早衰老和活性氧的产生。这些效应伴随着对过早衰老相关基因、和的调节。此外，GW501516激活的PPARδ几乎完全消除了HG处理对磷酸化H2A组蛋白家族成员X（γ-H2A.X）灶形成的影响，γ-H2A.X是衰老的分子标志物。在稳定表达靶向PPARδ的小发夹RNA的ARPE-19细胞中，GW501516的这些抑制作用显著逆转。值得注意的是，GW501516显著增加了SIRT1的mRNA和蛋白水平，表明GW501516激活的PPARδ通过SIRT1发挥其有益作用。此外，GW501516恢复了HG抑制的SIRT1表达，证实了SIRT1在PPARδ抗衰老功能中的作用。SIRT1激活剂白藜芦醇模拟了PPARδ对HG诱导的过早衰老和衰老相关基因p53、p21和SMP-30表达的影响，但被SIRT1抑制剂sirtinol阻断。总体而言，这些结果表明，GW501516激活的PPARδ通过调节SIRT1信号传导抑制HG触发的RPE细胞过早衰老。
