Modulation of PPARγ Provides New Insights in a Stress Induced Premature Senescence Model
Modulation of PPARγ Provides New Insights in a Stress Induced Premature Senescence Model
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DOI：
10.1371/journal.pone.0104045
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发表时间：
2014-08-07
期刊：
影响因子：
3.7
通讯作者：
Picardo, Mauro
中科院分区：
文献类型：
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作者：
Briganti, Stefania;Flori, Enrica;Picardo, Mauro
过氧化物酶体增殖物激活受体γ (PPAR γ)可能参与皮肤衰老过程的关键机制，影响皮肤细胞衰老相关的几个方面，包括抗氧化失衡。因此，我们研究了该核受体的上调是否在应激诱导的早衰（SIPS）模型中发挥保护作用，该模型基于8-甲氧基补骨脂素+紫外线a照射（PUVA）的人类真皮成纤维细胞单次暴露。在可能的PPAR γ调节剂中，我们选择了2,4,6-八烯酸（Octa），它是parrodiene家族的一员，之前报道过通过PPAR γ激活机制促进正常人类黑素细胞的黑色素生成和抗氧化防御。暴露于PUVA诱导PPAR γ表达和活性早期显著降低。PPAR γ上调抵消了PUVA诱导的抗氧化失衡，并通过细胞抗氧化网络中过氧化氢酶和还原性谷胱甘肽等不同组分的协同增加，降低了应激反应基因的表达。在Octa存在的情况下，puva处理的成纤维细胞部分但显著地摆脱了细胞衰老样表型的特征，如细胞质增大、衰老相关β -半乳糖苷酶、基质金属蛋白酶-1和细胞周期蛋白的表达。此外，细胞膜脂质的改变，如磷脂中多不饱和脂肪酸含量的减少和胆固醇水平的升高，这些是细胞衰老的典型特征，也被阻止了。我们的数据表明PPAR γ是PUVA-SIPS的靶点之一，其药理学上调可能代表一种新的治疗光氧化性皮肤损伤的方法。
Peroxisome proliferator-activated receptor gamma (PPAR gamma) may be involved in a key mechanism of the skin aging process, influencing several aspects related to the age-related degeneration of skin cells, including antioxidant unbalance. Therefore, we investigated whether the up-modulation of this nuclear receptor exerts a protective effect in a stress-induced premature senescence (SIPS) model based on a single exposure of human dermal fibroblasts to 8-methoxypsoralen plus + ultraviolet-A-irradiation (PUVA). Among possible PPAR gamma modulators, we selected 2,4,6-octatrienoic acid (Octa), a member of the parrodiene family, previously reported to promote melanogenesis and antioxidant defense in normal human melanocytes through a mechanism involving PPAR gamma activation. Exposure to PUVA induced an early and significant decrease in PPAR gamma expression and activity. PPAR gamma up-modulation counteracted the antioxidant imbalance induced by PUVA and reduced the expression of stress response genes with a synergistic increase of different components of the cell antioxidant network, such as catalase and reduced glutathione. PUVA-treated fibroblasts grown in the presence of Octa are partially but significantly rescued from the features of the cellular senescence-like phenotype, such as cytoplasmic enlargement, the expression of senescence-associated-beta-galactosidase, matrix-metalloproteinase-1, and cell cycle proteins. Moreover, the alterations in the cell membrane lipids, such as the decrease in the polyunsaturated fatty acid content of phospholipids and the increase in cholesterol levels, which are typical features of cell aging, were prevented. Our data suggest that PPAR gamma is one of the targets of PUVA-SIPS and that its pharmacological up-modulation may represent a novel therapeutic approach for the photooxidative skin damage.