Simvastatin Protects Human Melanocytes from H2O2-Induced Oxidative Stress by Activating Nrf2 Yuqian Chang, Shuli Li, Weinan Guo, Yuqi Yang, Weigang Zhang,

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Simvastatin Protects Human Melanocytes from H2O2-Induced Oxidative Stress by Activating Nrf2 Yuqian Chang, Shuli Li, Weinan Guo, Yuqi Yang, Weigang Zhang, Qian Zhang, Yuanmin He, Xiuli Yi, Tingting Cui, Yawen An, Pu Song, Zhe Jian, Ling Liu, Kai Li, Gang Wang, Tianwen Gao, Lin Wang, Chunying Li Journal of Investigative Dermatology Volume 137, Issue 6, Pages 1286-1296 (June 2017) DOI: 10.1016/j.jid.2017.01.020 Copyright © 2017 The Authors Terms and Conditions

Figure 1 Simvastatin ameliorates H2O2-induced oxidative damage in human melanocytes. (a, b) Melanocytes were treated with different concentrations of simvastatin for indicated times. (a) Cell proliferation and (b) viability were determined by CCK8 assay. (c–e) Melanocytes were pretreated with different concentrations of simvastatin for 24 hours and then exposed to 1.0 mmol/L H2O2 for another 24 hours. The morphological features of melanocytes were detected by microscope. Each field shown is a representative image of at least nine similar fields from three independent experiments, Scale bar = 200 μm in c. (d) Cell viability and (e) apoptosis determined by CCK-8 and flow cytometry assay, respectively. All data are presented as the mean ± standard deviation across three independent experiments. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. h, hour; H2O2, hydrogen peroxide; M, mol/L; Sim, simvastatin. Journal of Investigative Dermatology 2017 137, 1286-1296DOI: (10.1016/j.jid.2017.01.020) Copyright © 2017 The Authors Terms and Conditions

Figure 2 Simvastatin potentiates the antioxidant capacity of H2O2-treated human melanocytes. Melanocytes were exposed to various concentrations of simvastatin for 24 hours and were further treated with 1.0 mmol/L H2O2 for another 24 hours. (a) Intracellular ROS production determined by flow cytometry assay. The fluorescence intensity of ROS level is shown to the right. (b, c) The activity of antioxidant enzymes CAT and SOD. Error bars represent mean ± standard deviation across three independent experiments. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. CAT, catalase; DCF, dichlorodihydrofluorescein; H2O2, hydrogen peroxide; M, mol/L; ns, not significant; Sim, simvastatin; SOD, superoxide dismutase. Journal of Investigative Dermatology 2017 137, 1286-1296DOI: (10.1016/j.jid.2017.01.020) Copyright © 2017 The Authors Terms and Conditions

Figure 3 Simvastatin promotes the activation of Nrf2 and the expression of its downstream genes in H2O2-treated melanocytes. Melanocytes were exposed to different concentrations of simvastatin for 24 hours and were further treated with 1.0 mmol/L H2O2 for another 24 hours. (a) Nrf2 mRNA level analyzed by qRT-PCR. (b) Western blots of total, nuclear, and cytoplasmic fractions of Nrf2. The intensity of each band was quantified by densitometry analysis. The ratio of nuclear/cytosolic of Nrf2 is shown to the right. (c) The expression and nuclear translocation of phosphorylated Nrf2 determined by immunofluorescence. Scale bar = 10 μm. (d) The mRNA levels of HO-1 and NQO1 analyzed by qRT-PCR. (e) Western blots of HO-1 and NQO1. All data are expressed as mean ± standard deviation across three independent cultures. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. H2O2, hydrogen peroxide; M, mol/L; ns, not significant; p-, phosphorylated; qRT-PCR, quantitative real-time PCR; Sim, simvastatin. Journal of Investigative Dermatology 2017 137, 1286-1296DOI: (10.1016/j.jid.2017.01.020) Copyright © 2017 The Authors Terms and Conditions

Figure 4 Nrf2 activation is required for the protective effect of simvastatin on H2O2-treated melanocytes. Melanocytes were transfected with shRNA against Nrf2 or control shRNA for 24 hours and were then treated with 1.0 μmol/L simvastatin for 24 hours followed by 1.0 mmol/L H2O2 for another 24 hours. (a) Western blot analysis of Nrf2, HO-1, and NQO1. (b, c) The activity of CAT and SOD. (d) Intracellular ROS production analyzed by flow cytometry. The fluorescence intensity of ROS level is reported to the right. (e) Cell viability determined by CCK-8 assay. (f) The level of apoptosis detected by flow cytometry. Bar graphs represent the mean values of three independent flow cytometry data. Data are presented as the mean ± standard deviation. ∗∗P < 0.01, ∗∗∗P < 0.001. H2O2, hydrogen peroxide; M, mol/L; NC, normal control; shRNA, short hairpin RNA; Sim, simvastatin. Journal of Investigative Dermatology 2017 137, 1286-1296DOI: (10.1016/j.jid.2017.01.020) Copyright © 2017 The Authors Terms and Conditions

Figure 5 Mutual enhancement between MAPK pathway and p62 contributes to the activation of Nrf2 by simvastatin. (a) Western blots of the MAPK pathway. (b, c) Western blots of Nrf2 and p-Nrf2 in melanocytes pretreated with (b) PD98059 and (c) SP600125 and then treated with simvastatin followed by H2O2. (d) Protein level of p62 in simvastatin pretreated H2O2-treated melanocytes. (e) Western blots of Nrf2 in melanocytes transfected with siRNA-p62 for 24 hours and then treated with simvastatin followed by H2O2. (f, g) Western blots of p62 in melanocytes pretreated with (f) PD98059 and (g) SP600125 and then treated with simvastatin and H2O2. (h) Western blots of p-Erk and p-JNK in melanocytes transfected with siRNA-p62 and then treated with simvastatin and H2O2. Erk, extracellular signal-regulated kinase; H2O2, hydrogen peroxide; JNK, c-Jun N-terminal kinase; M, mol/L; NC, normal control; p-, phosphorylated; Sim, simvastatin; siRNA, small interfering RNA. Journal of Investigative Dermatology 2017 137, 1286-1296DOI: (10.1016/j.jid.2017.01.020) Copyright © 2017 The Authors Terms and Conditions

Figure 6 Simvastatin has better antioxidative capacity than aspirin in H2O2-treated melanocytes. Melanocytes were exposed to either simvastatin (1.0 μmol/L) or aspirin (90.0 μmol/L) for 24 hours and were then treated with 1.0 mmol/L H2O2 for another 24 hours. (a) Cell apoptosis analyzed by flow cytometry. (b) Cell viability determined by CCK-8 assay. (c) Intracellular ROS production determined by flow cytometry. The fluorescence intensity of ROS level is shown to the right. (d, e) The activity of CAT and SOD. (f) Western blots of Nrf2, p-Nrf2, and HO-1 in melanocytes pretreated with either simvastatin or aspirin alone or together and then treated with H2O2. All data are presented as the mean ± standard deviation of three independent experiments. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. ASA, aspirin; DCF, dichlorodihydrofluorescein; H2O2, hydrogen peroxide; M, mol/L; ns, not significant; p-, phosphorylated; Sim, simvastatin. Journal of Investigative Dermatology 2017 137, 1286-1296DOI: (10.1016/j.jid.2017.01.020) Copyright © 2017 The Authors Terms and Conditions