TY - JOUR
T1 - Simvastatin attenuates oxidative stress, NF-κB activation, and artery calcification in LDLR-/-mice fed with high fat diet via down-regulation of tumor necrosis factor-α and TNF receptor 1
AU - Lin, Chih Pei
AU - Huang, Po Hsun
AU - Lai, Chung Fang
AU - Chen, Jaw Wen
AU - Lin, Shing Jong
AU - Chen, Jia Shiong
N1 - Publisher Copyright:
© 2015 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Simvastatin (SIM) is anti-inflammatory. We used low density lipoprotein receptor knockout (LDLR-/-) mice and human aortic smooth muscle cells (HASMCs) as model systems to study the effect of SIM on arterial calcification and to explore the potential mechanisms contributing to this protective effect. High-fat diet (HFD) caused the LRLR-/-to develop dyslipidemia, diabetics, atherosclerosis and aortic smooth muscle calcification. SIM, N-Acetyl cysteine (NAC, a ROS scavenger) and apocynin (APO, a NADPH oxidase inhibitor) did not significantly retard the development of dyslipidemia or diabetic. However, those treatments were still effective in attenuating the HFD-induced atherosclerosis and aortic smooth muscle calcification. These findings suggest that the protective effect of SIM against aortic calcification is not contributed by the cholesterol lowering effect. SIM, NAC and APO were found to attenuate the HFD induced elevation of serum TNF-α, soluble TNFR1 (sTNFR1), 3-nitrotyrosine. We hypothesized that the pro-inflammatory cytokine, oxidative stress and TNFR1 played a role in inducing aortic calcification.We used HASMC to investigate the role of TNF-α, oxidative stress and TNFR1 in inducing aortic calcification and to elucidate the mechanism contributes the protective effect of SIM against aortic calcification. We demonstrated that treating HASMC with TNF-α induced cell Ca deposit and result in an increase in ALP, NADPH oxidase activity, NF-kB subunit p65, BMP2, MSX2, and RUNX2 expression. SIM suppressed the TNF-α induced activation of NADPH oxidase subunit p47, the abovementioned bone markers and TNFR1 expression. Furthermore, p65, p47 and TNFR1 siRNAs inhibited the TNF-α-mediated stimulation of BMP-2, MSX2, RUNX2 expression. SIM, APO, and NAC either partially inhibit or completely block the TNF-α induced H 2 O 2 or superoxide production. These results suggest that SIM may, independent of its cholesterollowering effect, suppresses the progression of vascular diseases through the inhibition of the inflammation mediators TNF-α and TNFR1.
AB - Simvastatin (SIM) is anti-inflammatory. We used low density lipoprotein receptor knockout (LDLR-/-) mice and human aortic smooth muscle cells (HASMCs) as model systems to study the effect of SIM on arterial calcification and to explore the potential mechanisms contributing to this protective effect. High-fat diet (HFD) caused the LRLR-/-to develop dyslipidemia, diabetics, atherosclerosis and aortic smooth muscle calcification. SIM, N-Acetyl cysteine (NAC, a ROS scavenger) and apocynin (APO, a NADPH oxidase inhibitor) did not significantly retard the development of dyslipidemia or diabetic. However, those treatments were still effective in attenuating the HFD-induced atherosclerosis and aortic smooth muscle calcification. These findings suggest that the protective effect of SIM against aortic calcification is not contributed by the cholesterol lowering effect. SIM, NAC and APO were found to attenuate the HFD induced elevation of serum TNF-α, soluble TNFR1 (sTNFR1), 3-nitrotyrosine. We hypothesized that the pro-inflammatory cytokine, oxidative stress and TNFR1 played a role in inducing aortic calcification.We used HASMC to investigate the role of TNF-α, oxidative stress and TNFR1 in inducing aortic calcification and to elucidate the mechanism contributes the protective effect of SIM against aortic calcification. We demonstrated that treating HASMC with TNF-α induced cell Ca deposit and result in an increase in ALP, NADPH oxidase activity, NF-kB subunit p65, BMP2, MSX2, and RUNX2 expression. SIM suppressed the TNF-α induced activation of NADPH oxidase subunit p47, the abovementioned bone markers and TNFR1 expression. Furthermore, p65, p47 and TNFR1 siRNAs inhibited the TNF-α-mediated stimulation of BMP-2, MSX2, RUNX2 expression. SIM, APO, and NAC either partially inhibit or completely block the TNF-α induced H 2 O 2 or superoxide production. These results suggest that SIM may, independent of its cholesterollowering effect, suppresses the progression of vascular diseases through the inhibition of the inflammation mediators TNF-α and TNFR1.
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U2 - 10.1371/journal.pone.0143686
DO - 10.1371/journal.pone.0143686
M3 - Article
C2 - 26625143
AN - SCOPUS:84961289252
SN - 1932-6203
VL - 10
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - 0143686
ER -
