作者机构：
[林丽美; 柏玉冰; 夏伯候; 周亚敏; 谢嘉驰; 李亚梅; 严东; 廖端芳; 曹艺] College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China;[林丽美; 柏玉冰; 夏伯候; 周亚敏; 谢嘉驰; 李亚梅; 严东; 廖端芳; 曹艺] Hunan Research Center of Engineering Technology for Rapid Test and Removal of Toxic and Harmful Substances in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China;[林丽美; 柏玉冰; 夏伯候; 周亚敏; 谢嘉驰; 李亚梅; 严东; 廖端芳; 曹艺] Hunan Engineering Laboratory for Prevention and Control Technology of Toxic Substances in Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
作者机构：
[Zeng, Heng; Chen, Jian-xiong; He, Xiaochen] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Sch Med, Jackson, MS 39216 USA.;[Liao, Duan-fang; Tuo, Qin-hui] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Changsha 410208, Hunan, Peoples R China.;[Zhang, Guo-qiang] China Japan Friendship Hosp, Emergency Dept, Beijing 100029, Peoples R China.
通讯机构：
[Chen, Jian-xiong] U;Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Sch Med, Jackson, MS 39216 USA.
摘要：
Recent studies reveal a crucial role of pericyte loss in sepsis-associated microvascular dysfunction. Sirtuin 3 (SIRT3) mediates histone protein post-translational modification related to aging and ischemic disease. This study investigated the involvement of SIRT3 in LPS-induced pericyte loss and microvascular dysfunction. Mice were exposed to LPS, expression of Sirt3, HIF-2α, Notch3 and angiopoietins/Tie-2, pericyte/endothelial (EC) coverage and vascular permeability were assessed. Mice treated with LPS significantly reduced the expression of SIRT3, HIF-2α and Notch3 in the lung. Furthermore, exposure to LPS increased Ang-2 while inhibited Ang-1/Tie-2 expression with a reduced pericyte/EC coverage. Intriguingly, knockout of Sirt3 upregulated Ang-2, but downregulated Tie-2 and HIF-2α/Notch3 expression which resulted in a dramatic reduction of pericyte/EC coverage and exacerbation of LPS-induced vascular leakage. Conversely, overexpression of Sirt3 reduced Ang-2 expression and increased Ang-1/Tie-2 and HIF-2α/Notch3 expression in the LPS treated mice. Overexpression of Sirt3 further prevented LPS-induced pericyte loss and vascular leakage. This was accompanied by a significant reduction of the mortality rate. Specific knockout of prolyl hydroxylase-2 (PHD2) increased HIF-2α/Notch3 expression, improved pericyte/EC coverage and reduced the mortality rate in the LPS-treated mice. Our study demonstrates the importance of SIRT3 in preserving vascular integrity by targeting pericytes in the setting of LPS-induced sepsis.
作者机构：
[Gu, Hong-Feng; Tang, Xiao-Qing; Tang, Ya-Ling] Univ South China, Dept Physiol, Hengyang, Peoples R China.;[Gu, Hong-Feng; Tang, Xiao-Qing; Tang, Ya-Ling] Univ South China, Inst Neurosci, Hengyang, Peoples R China.;[Li, Hai-Zhe] Univ South China, Affiliated Hosp 1, Dept Neurol, Hengyang, Peoples R China.;[Zheng, Xi-Long] Univ Calgary, Fac Med, Libin Cardiovasc Inst Alberta, Smooth Muscle Res Grp,Dept Biochem & Mol Biol, Calgary, AB, Canada.;[Zheng, Xi-Long; Liao, Duan-Fang] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha, Hunan, Peoples R China.
通讯机构：
[Liao, Duan-Fang] H;Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha, Hunan, Peoples R China.
摘要：
Our previous studies have indicated that a novel curcumin derivate nicotinate-curcumin (NC) has beneficial effects on the prevention of atherosclerosis, but the precise mechanisms are not fully understood. Given that autophagy regulates lipid metabolism, the present study was designed to investigate whether NC decreases foam cell formation through restoring autophagy flux in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells. Our results showed that ox-LDL (100 μg/ml) was accumulated in THP-1 cells and impaired autophagy flux. Ox-LDL-induced impairment of autophagy was enhanced by treatment with the autophagy inhibitor chloroquine (CQ) and rescued by the autophagy inducer rapamycin. The aggregation of ox-LDL was increased by CQ, but decreased by rapamycin. In addition, colocalization of lipid droplets with LC3-II was remarkably reduced in ox-LDL group. In contrast, NC (10 μM) rescued the impaired autophagy flux by significantly increasing level of LC3-II, the number of autophagolysosomes, and the degradation of p62 in ox-LDL-treated THP-1 cells. Inhibition of the PI3K-Akt-mTOR signaling was required for NC-rescued autophagy flux. Notably, our results showed that NC remarkably promoted the colocalization of lipid droplets with autophagolysosomes, increased efflux of cholesterol, and reduced ox-LDL accumulation in THP-1 cells. However, treatment with 3-methyladenine (3-MA) or CQ reduced the protective effects of NC on lipid accumulation. Collectively, the findings suggest that NC decreases lipid accumulation in THP-1 cells through restoring autophagy flux, and further implicate that NC may be a potential therapeutic reagent to reverse atherosclerosis.
作者机构：
1. 湖南中医药大学中药粉体与创新药物国家重点实验室培育基地;2. Department of Medical Microbiology, Immunology & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine
期刊：
Medical Hypotheses,2016年86:138-142 ISSN：0306-9877
通讯作者：
Liao, Duan-fang
作者机构：
[Zhang, Cai-ping] Univ South China, Coll Med, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Liao, Duan-fang; Chen, Jian-xiong; Tuo, Qin-hui] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Div Stem Cell Regulat & Applicat, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.;[Tian, Ying; Zhang, Cai-ping; Zhang, Min] Univ South China, Dept Biochem & Mol Biol, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Chen, Jian-xiong] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, University, MS 38677 USA.;[Liao, Duan-fang] Hunan Univ Chinese Med, 1 Xiangzui Rd, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Liao, Duan-fang] H;Hunan Univ Chinese Med, 1 Xiangzui Rd, Changsha 410208, Hunan, Peoples R China.
摘要：
Low-density lipoprotein cholesterol (LDL-C) is the hall marker for the atherosclerotic cardiovascular disease (ASCVD). It has been shown that over 70% of circulating LDL-C is metabolized through binding and activation of hepatic LDL receptor (LDLR). Genetic LDLR mutations cause hypercholesterolemia in the patients. Therefore, elevation of LDLR levels is beneficial for the treatment of dyslipidemia. LDLR expression is regulated by the SREBP2/PCSK9 pathways. Targeting SREBP2/PCSK9 pathways by statins and human monoclonal PCSK9 antibody has been shown to reduce the progression of ASVCD. Recent studies identified that inducible degrader of LDLR (IDOL) is a novel regulator of LDLR. IDOL is an E3-ubiquitin ligase regulated via liver X receptors (LXRs) binding to the upstream of translation start site of IDOL. IDOL modulates LDLR distribution through ubiquitination and degradation of LDLR in lysosomes. Genome-wide association studies (GWAS) have revealed that the nonsynonymous substitution rs9370867 of IDOL probably contributes to the variability of circulating LDL levels. Recently studies also demonstrated that IDOL influences PCSK9 expression in a LDLR/SREBP2-dependent manner. Based upon these novel findings, we hypothesize that IDOL and PCSK9 would have a synergistic effect on LDLR distribution. Specifically, loss of IDOL increases LDLR distribution in the hepatic cell, and subsequently reduces serum LDL-C levels in dyslipidemic patients. IDOL might be a potential therapeutic target for the treatment of ASCVD. (C) 2015 Elsevier Ltd. All rights reserved.
