Activation of Nrf2 Reduces UVA-Mediated MMP-1 Upregulation via MAPK/AP-1 Signaling Cascades: The Photoprotective Effects of Sulforaphane and Hispidulin.
Activation of Nrf2 Reduces UVA-Mediated MMP-1 Upregulation via MAPK/AP-1 Signaling Cascades: The Photoprotective Effects of Sulforaphane and Hispidulin.
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DOI：
10.1124/jpet.116.238048
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发表时间：
2017-03
期刊：
影响因子：
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通讯作者：
Panich U
中科院分区：
文献类型：
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作者：
Chaiprasongsuk A;Lohakul J;Soontrapa K;Sampattavanich S;Akarasereenont P;Panich U
UVA照射通过触发与氧化应激相关的基质金属蛋白酶-1 （MMP-1）的刺激，在皮肤过早衰老中起作用，基质金属蛋白酶-1负责胶原蛋白降解，这是光老化皮肤的标志。因此，能够激活调控抗氧化基因表达的转录因子核因子e2相关因子2 （Nrf2）的化合物应该是有效的抗光老化剂。我们利用人角质形成细胞系（HaCaT）研究了Nrf2基因沉默是否可以通过激活丝裂原活化蛋白激酶(MAPK)/激活蛋白1 （AP-1）信号通路来缓解uva介导的MMP-1上调。利用重复UVA照射的BALB/c小鼠皮肤，评估hispidulin （HPD）和萝卜硫素（SFN）在控制MMP-1和胶原蛋白表达与MAPKs（细胞外信号调节激酶、c- jun n -末端激酶和p38）、c- jun和c- fos磷酸化方面激活Nrf2的抗光老化作用。我们的研究结果表明，在uva照射的HaCaT细胞中，Nrf2的缺失促进了mRNA的表达和MMP-1的活性。用MAPK抑制剂处理Nrf2敲低的HaCaT细胞可显著抑制uva诱导的MMP-1和AP-1活性。此外，用HPD和SFN预处理小鼠皮肤，可以激活Nrf2，对uva介导的MMP-1诱导和胶原消耗具有保护作用，这与小鼠皮肤中磷酸化MAPKs、c-Jun和c-Fos的水平降低有关。综上所述，Nrf2可以通过MAPK/AP-1信号级联影响uva介导的MMP-1上调。因此，HPD和SFN可能是有希望的抗光老化候选者。
UVA irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds that can activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant gene expression, should therefore serve as effective antiphotoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling using human keratinocyte cell line (HaCaT). Antiphotoaging effects of hispidulin (HPD) and sulforaphane (SFN) were assessed on their abilities to activate Nrf2 in controlling MMP-1 and collagen expressions in association with phosphorylation of MAPKs (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38), c-Jun, and c-Fos, using the skin of BALB/c mice subjected to repetitive UVA irradiation. Our findings suggested that depletion of Nrf2 promoted both mRNA expression and activity of MMP-1 in the UVA-irradiated HaCaT cells. Treatment of Nrf2 knocked-down HaCaT cells with MAPK inhibitors significantly suppressed UVA-induced MMP-1 and AP-1 activities. Moreover, pretreatment of the mouse skin with HPD and SFN, which could activate Nrf2, provided protective effects against UVA-mediated MMP-1 induction and collagen depletion in correlation with the decreased levels of phosphorylated MAPKs, c-Jun, and c-Fos in the mouse skin. In conclusion, Nrf2 could influence UVA-mediated MMP-1 upregulation through the MAPK/AP-1 signaling cascades. HPD and SFN may therefore represent promising antiphotoaging candidates.