作者机构：
[Qu, Kai] 3 College of Bioengineering, Chongqing University , Chongqing, China;[Chen, Jiaojiao; Liu, Yami; Zeng, Zhaolin; Wang, Zuo; Wei, Dangheng] 1 Key Laboratory for Atherosclerology of Hunan Province, Institute of Cardiovascular Disease, University of South China , Hengyang, China;[Peng, Wen] 2 Department of Spine Surgery, The First Affiliated Hospital, University of South China , Hengyang, China;[Lin, Xiaolong] 4 Department of Pathology, The Third People's Hospital of Huizhou , Huizhou, China
摘要：
Atherosclerosis is the underlying cause of cardio-cerebrovascular disease. However, the mechanisms of atherosclerosis are still unclear. The modification of DNA methylation has an important role in atherosclerosis development. As a member of the Ten-eleven translocation (TET) family, TET methylcytosine dioxygenase 2 (TET2) can modify DNA methylation by catalyzing 5-methylcytosine to 5-hydroxymethylcytosine and mediate DNA demethylation. Recent findings suggest that TET2 is related to the phenotype transformation of vascular smooth muscle cells, endothelial dysfunction, and inflammation of macrophage, the key factors of atherosclerosis. Therefore, TET2 may be a potential target for atherosclerosis treatment. This review will elaborate the recent findings that suggest the role of TET2 in atherosclerosis.
作者机构：
[Jiang, Zhi-Sheng] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China. Electronic address: zsjiang2005@163.com;[Ren, Zhong; Tang, Zhi-Han; Li, Tao-Hua; Wei, Dang-Heng; Peng, Juan; Li, Ting-Ting; Wang, Zuo; Liu, Lu-Shan] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China;[Tang, Zhi-Han] Laboratory of Experimental Surgery, University of South China, Hengyang, Hunan 421001, China;[Zheng, Xi-Long] Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada;[Yang, Jing] Laboratory of Clinical Research, University of South China, Hengyang, 421001, China
通讯机构：
[Jiang, Zhi-Sheng] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.
关键词：
PCSK9;Atherosclerosis;Inflammation;Macrophage;TLR4/ /NF-kappa B
摘要：
Background and aims: Proprotein convertase subtilisin/kexin 9 (PCSK9) has emerged as a popular target in the development of new cholesterol-lowering drugs and therapeutic interventions for atherosclerosis. PCSK9 could accelerate atherosclerosis through mechanisms beyond the degradation of the hepatic lowdensity lipoprotein receptor. Several clinical studies suggested that PCSK9 is involved in atherosclerotic inflammation. Accordingly, this study aimed to explore the role of PCSK9 in vascular inflammation that promotes atherosclerotic progression. Methods: We examined whether PCSK9 silencing via transduction with the lentivirus-mediated PCSK9 shRNA (LV-PCSK9 shRNA) vector affects the formation of vascular lesions in hyperlipidemia-induced atherosclerosis in apolipoprotein E knockout (apoE KO) mice. In vitro, the effects of PCSK9 on oxLDLinduced macrophages inflammation were investigate using LV-PCSK9 and LV-PCSK9 shRNA for PCSK9 overexpression and PCSK9 silencing. Results: Immunohistochemical analysis showed that PCSK9 expression increased within atherosclerotic plaques in apoE KO mice. These in vivo results showed that the LV-PCSK9 shRNA group of mice developed less aortic atherosclerotic plaques compared with the control group. These lesions also had the reduced number of macrophages and decreased expression of vascular inflammation regulators, such as tumor necrosis factor-alpha, interleukin 1 beta, monocyte chemoattractant protein-1, toll-like receptor 4 and nuclear factor kappa B (NF-kappa B). We further showed that PCSK9 overexpression in macrophages in vitro increased the secretion of oxLDL-induced proinflammatory cytokines. PCSK9 overexpression upregulated TLR4 expression and increased p-I kappa B alpha levels, IkB alpha degradation, and NF-kappa B nuclear translocation in macrophages, but PCSK9 knockdown had the opposite effects in oxLDL-treated macrophages. Conclusions: PCSK9 gene interference could suppress atherosclerosis directly through decreasing vascular inflammation and inhibiting the TLR4/NF-kappa B signaling pathway without affecting plasma cholesterol level in high-fat diet-fed apoE KO mice. PCSK9 may be an inflammatory mediator in the pathogenesis of atherosclerosis. (C) 2017 Elsevier B.V. All rights reserved.
作者机构：
Bioengineering College and “111 Project” Laboratory of Biomechanics and Tissue Repair, Chongqing University, Chongqing, 400044 China;The Institute of Cardiovascular Disease, Nanhua University, Heng Yang, China
摘要：
Oxidized low-density lipoprotein (ox-LDL) is an independent risk factor of atherosclerosis. However, the mechanism underlying its pro-atherosclerosis roles has not yet been well explored. DNA demethylation modification, via DNA methyltransferases or ten-eleven-translocation (TET) family, is a crisis epigenetic regulation for various biological and pathological processes. This study aimed to investigate the effects of ox-LDL on macrophage autophagy and its potential epigenetic mechanism. Results showed that after treatment with 0, 10, 20, 40 or 80 mg/L ox-LDL for 24 h, the autophagy markers Beclin 1 and LC3 expression were obviously decreased at protein levels (P < 0.05). The mRNA and protein expression of TET2 was evidently decreased (P < 0.05). After pre-treatment with TET2 siRNA, the mRNA and protein levels of Beclin 1 and LC3 decreased compared with the 80 mg/L treatment group (P < 0.01). The mRNA and protein levels of Beclin 1 and LC3-II were up-regulated (P < 0.05) in the 5-aza-2'-deoxycytidine (a DNA methyltransferase inhibitor) of pretreatment group. Consistent with the Western blot results, cell immunofluorescence showed that the protein concentration of LC3-II decreased in the TET2 siRNA group and increased in the 5-aza-2'-deoxycytidine group. Taken together, these results showed that DNA demethylation modifications regulate ox-LDL-treated THP-1 macrophages autophagy and TET2 might be a novel regulator.
期刊：
MOLECULAR MEDICINE REPORTS,2013年7(6):1865-1870 ISSN：1791-2997
通讯作者：
Jiang, Zhi-Sheng
作者机构：
[Jiang, Zhi-Sheng] Univ South China, Inst Cardiovasc Dis, Hengyang 421001, Hunan, Peoples R China.;[Jiang, Zhi-Sheng] Univ South China, Inst Cardiovasc Dis, 28 Changsheng West Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Jiang, Zhi-Sheng] Univ South China, Inst Cardiovasc Dis, 28 Changsheng West Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
sirtuin 1;oxidative stress;cardiovascular
摘要：
The aim of the present study was to investigate the attenuation of endothelial cell senescence by H2S and to explore the mechanisms underlying the anti-aging effects of H2S. Senescence was induced in human umbilical vein endothelial cells (HUVECs) by incubation in 25 micromol/l H2O2 for 1 h. Senescence-associated beta-galactosidase (SA-beta-gal) activity was examined to determine the effects of H2S on senescent HUVECs. The results indicated that SA-beta-gal activity in the H2O2-treated HUVECs was 11.2 +/- 1.06%, which was attenuated in the NaHS group. Pretreatment with nicotinamide (NAM), a sirtuin 1 (SIRT1) inhibitor, inhibited the reduction in senescence associated with H2S. Immunoblot analyses revealed that SIRT1 levels in senescent HUVECs treated with NaHS (60 microM) were indistinguishable from controls; however, analyses of SIRT1 activity indicated that SIRT1 enzyme activity was enhanced. In addition, we found that H2S improves the function of senescent HUVECs. The present study demonstrated that H2S protects against HUVEC senescence, potentially through modulation of SIRT1 activity. Furthermore, this study establishes a novel endothelial protective effect of H2S.
作者机构：
[Zeng, Jun-fa; Zhang, Kai] The Second Hospital Affiliated to University of South China, Hengyang, Hunan 421001, PR China;[Zeng, Zhao-lin; Zhao, Yue; Liu, Ya-mi; Chen, Jiao-jiao; Wei, Dang-heng; Jiang, Zhi-sheng; Wang, Zuo] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, PR China;[Tong, Hai] The First Hospital Affiliated to University of South China, Hengyang, Hunan 421001, PR China
通讯机构：
[Wang, Zuo] Univ South China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.
摘要：
High concentrations of plasma lipoprotein(a) [Lp(a)] have been inferred to be an independent risk factor for cardiovascular and cerebrovascular diseases, such as coronary artery diseases, restenosis, and stroke. Apolipoprotein(a) [apo(a)] is one of the most important components of Lp(a) and contributes greatly to the increased concentration of plasma Lp(a). As a critical positive transacting factor of apo(a) gene, Ets1 has been proven as a target gene of several miRNAs, such as miR‐193b, miR‐125b‐5p, miR‐200b, miR‐1, and miR‐499. In this study, a series of experiments on miRNAs and relative miRNAs inhibitor delivered HepG2 cells were conducted, and two miRNAs that downregulate the apo(a) by targeting the 3′‐UTR of Ets1 were identified. Results showed that apo(a) and Ets1 were differentially expressed in SMMC7721 and HepG2 cell lines. Meanwhile, apo(a) and Ets1 were inversely correlated with several hepatic endogenous miRNAs, such as miR‐125b‐5p, miR‐23b‐3p, miR‐26a‐5p, and miR‐423‐5p, which were predicted to bind to Ets1. Results show that miR‐125b‐5p and miR‐23b‐3p mimics could inhibit the synthesis of apo(a) by directly targeting Ets1 in HepG2, thereby reducing the plasma Lp (a) concentration.
期刊：
DNA and cell biology,2017年36(11):883-891 ISSN：1044-5498
通讯作者：
Wei, DH;Wang, Y
作者机构：
[Li, Afang; Peng, Wenxi; Xia, Xiaodan; Li, Rongqing; Wei, Dangheng] 1 Institute of Cardiovascular disease, Key Laboratory for Atherosclerology of Hunan Province, University of South China , Hengyang, China;[Xia, Xiaodan] 2 Affiliated Nanhua Hospital of University of South China , Hengyang, China;[Wang, Yu] 3 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
通讯机构：
[Wei, Dangheng] Univ South China, Inst Cardiovasc Dis, Key Lab Atherosclerol Hunan Prov, Hengyang, Peoples R China.;[Wang, Yu] Huazhong Univ Sci & Technol, Dept Neurosurg, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China.
摘要：
Endothelial-to-mesenchymal transition (EndMT) is a cellular reprogramming mechanism by which endothelial cells acquire a mesenchymal phenotype. EndMT is associated with fibroproliferative diseases, such as cancer progression and metastasis and cardiac and kidney fibrosis, and this condition has been extensively investigated over the past decade. Recently, studies showed that EndMT contributes to the initiation and progression of atherosclerotic lesion and plaque destabilization. Unstable atherosclerotic plaque rupture and subsequent thrombosis are the main pathological causes of acute cardiovascular events. EndMT is plastic and reversible. Therefore, our enhanced understanding on the mechanisms controlling EndMT and its roles in the atherosclerosis plaque progression and instability may provide a basis for the development of novel therapeutic strategies to stabilize and reverse atherosclerotic plaques.
期刊：
Annals of Biomedical Engineering,2014年42(9):1978-1988 ISSN：0090-6964
通讯作者：
Wei, DH
作者机构：
[Wei, Dangheng; Wang, Gui-xue] Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College of Chongqing University, Chongqing 400044, China;[Guo, Fengxia; Liu, Lushan; Xiao, Ming; Ni, Chuyu; Jiang, Zhisheng; Yang, Qin; Wei, Dangheng; Peng, Juan; Tang, Yaling; Wang, Zuo; Chen, Ruixing; Li, Xiaohong] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China;[Guo, Fengxia] Second People Hospital of Heze City, Heze 274000, Shandong, China
通讯机构：
[Wei, Dangheng] Univ South China, Key Lab Arteriosclerol Hunan Prov, Inst Cardiovasc Dis, Hengyang 421001, Peoples R China.
