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：
[Li, Xiaohong; Chen, Ruixing; Wang, Zuo; Tang, Yaling; Peng, Juan; Wei, Dangheng; Yang, Qin; Jiang, Zhisheng; Ni, Chuyu; Xiao, Ming; Liu, Lushan; Guo, Fengxia] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China;[Wang, Gui-xue; Wei, Dangheng] Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College of Chongqing University, Chongqing 400044, China;[Guo, Fengxia] Second People Hospital of Heze City, Heze 274000, Shandong, China
通讯机构：
[Wei, DH] Univ South China, Key Lab Arteriosclerol Hunan Prov, Inst Cardiovasc Dis, Hengyang 421001, Peoples R China.
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：
[Wang, Y] Huazhong Univ Sci & Technol, Dept Neurosurg, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China.;[Wei, DH] Univ South China, Inst Cardiovasc Dis, Key Lab Atherosclerol Hunan Prov, Hengyang, 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.
作者机构：
[Liu, Lu-Shan; Wang, Zuo; Li, Ting-Ting; Peng, Juan; Wei, Dang-Heng; Li, Tao-Hua; Tang, Zhi-Han; Ren, Zhong] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China;[Yang, Jing] Laboratory of Clinical Research, University of South China, Hengyang, 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;[Tang, Zhi-Han] Laboratory of Experimental Surgery, University of South China, Hengyang, Hunan 421001, China;[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
通讯机构：
[Jiang, Zhi-Sheng] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China. Electronic address:
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.
期刊：
MOLECULAR MEDICINE REPORTS,2013年7(6):1865-1870 ISSN：1791-2997
通讯作者：
Jiang, ZS
作者机构：
[Suo, Rong] Institute of Cardiovascular Disease and Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China
通讯机构：
[Jiang, ZS] 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, Z] 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.
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：
Journal of Long-Term Effects of Medical Implants,2013年23(1):67-86 ISSN：1050-6934
通讯作者：
Guidoin, R.(Robert.Guidoin@gmail.com)
作者机构：
[Guidoin, Robert] Departments of Surgery and Radiology, Laval University and Qué[Guidoin, Robert] bec Biomaterials Institute, Quebec, QC, Canada;[Lin, Jing] Key Laboratory of Textile Science and Technology of Ministry of Education and College of Textiles, Donghua University, Shanghai, China;Department of Surgery, University of Calgary and Calgary Health Authority, Calgary AB, Canada;Energie, Maté
摘要：
Transmembrane 6 superfamily 2 (TM6SF2), a gene identified at the locus 19p12, has been recognized to regulate plasma lipids. Here, we provide an overview of the roles of TM6SF2 as a novel target for plasma lipid regulation. We first review the association of TM6SF2 variant with plasma lipid traits, cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). Then, we present an overview about the in vivo validation of TM6SF2 as a regulator of plasma lipid levels using mice, with overexpression or knockdown/knockout of TM6SF2. Thereafter, we discuss the mechanisms underlying TM6SF2 regulation of lipid metabolism involving intestinal cholesterol absorption and hepatic cholesterol biosynthesis and transport. In conclusion, increasing evidence suggests that TM6SF2 may be a major regulator of plasma lipid levels and become a therapeutic target in cardiovascular disease. (C) 2017 Elsevier B.V. All rights reserved.
通讯机构：
[Wei, Dang-Heng] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, P.R. China.
摘要：
The activation of endothelial cells by oxidized low-density lipoprotein (ox-LDL) with subsequent increases in endothelial permeability occurs in the early stage of atherosclerosis. Cathepsin L (CATL) is one of the cysteine proteases and has been implicated in advanced atherosclerotic lesions and plaque instability. This study aimed to explore the role of CATL in ox-LDL-induced early atherosclerotic events and to delineate the underlying mechanism. Results showed that ox-LDL upregulated CATL protein levels and activation in human umbilical vein endothelial cells (ECs) in a concentration-dependent manner and stimulated EC autophagy and apoptosis and increased EC monolayer permeability. Concomitantly, VE-cadherin expression was decreased. When ECs were pretreated with a CATL inhibitor, ox-LDL-induced autophagy was inhibited while apoptosis was further increased. In addition, the VE-cadherin protein level was increased, and the EC monolayer permeability was reduced. Taken together, the present study showed that the upregulated expression and activation of CATL induced by ox-LDL, increased EC autophagy and antagonized EC apoptosis, which partly neutralized the effect of increased EC monolayer permeability mediated by the downregulation of VE-cadherin. Thus, the proatherogenic effect of CATL was partly neutralized by inducing autophagy and inhibiting apoptosis in early stages of atherosclerosis.
期刊：
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES,2017年98:637-645 ISSN：0141-8130
通讯作者：
Wang, Z
作者机构：
[Zhang, Kai; Liu, Ya-mi; Zhang, Hai; Wei, Dang-heng; Li, Guo-hua; Ma, Xiao-feng; Lei, Jian-jun; Qu, Kai] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001 China;[Zhang, Kai] The Second Hospital Affiliated to University of South China, Hengyang 421001, Hunan, China;[Wang, Zuo] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001 China. Electronic address: smt121101@163.com;[Zeng, Jun-fa] The Second Hospital Affiliated to University of South China, Hengyang 421001, Hunan, China
通讯机构：
[Wang, Zuo] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001 China. Electronic address:
摘要：
Lipoprotein(a)[Lp(a)] is a risk factor for coronary heart diseases. However, the metabolism of this protein remains poorly understood. Efficient and specific drugs that can decrease high plasma levels of Lp(a) have not been developed yet. Vitamin C is responsible for maintaining the catalytic activity of a group of iron and 2-oxoglutarate (20G)-dependent dioxygenases and induces the generation of 5-hydroxymethylcytosine (5hmC) via Ten-eleven translocation (Tet) dioxygenases. In addition, It has been reported vitamin C deficiency induces atherosclerosis and increases Lp(a) and apo(a) plasma levels in Lp(a)(+) mice. However, the mechanism is still unclear. In this study, we investigated the effects of vitamin C on apo(a) expression and the possible molecular mechanism of vitamin C that influences apolipoprotein(a) [apo(a)] biosynthesis in HepG2 cells. Results showed that vitamin C significantly inhibited the expression and secretion levels of apo(a). Vitamin C can also increase ELK1 expression and hydroxymethylation of ELK1 promoter and the globle DNA in HepG2 cells. In addition, the effects of vitamin C inhibiting the apo(a) expression were attenuated by ELK1siRNA and Tet2siRNA. These results suggested vitamin C down-regulate apo(a) expression via Tet2-dependent DNA demethylation in HepG2 cells. (C) 2017 Elsevier B.V. All rights reserved.
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE,2015年35(5):1179-1188 ISSN：1107-3756
通讯作者：
Qu, P
作者机构：
[Wang, Xiaoqing; Peng, Kuang; Wang, Hongyan; He, Dan; Wang, Lili; Altaf, Afrasyab; Qu, Peng] Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China;[Wei, Dangheng; Lv, Yuncheng; Liu, Lushan] Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China;[Xiong, Wenhao] Medical College, University of South China, Hengyang, Hunan 421001, P.R. China;[Wang, Gang] Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
通讯机构：
[Qu, P] Dalian Med Univ, Affiliated Hosp 2, Dept Cardiol, 467 Zhongshan Rd, Dalian 116023, Liaoning, Peoples R China.
关键词：
protein kinase R;purinergic 2X7 receptor;nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome;atherosclerosis
摘要：
Purinergic 2X7 receptor (P2X7R) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) are expressed in macrophages in atherosclerotic lesions. However, the mechanisms through which P2X7R participates in the inflammatory response in atherosclerosis remain largely unknown. The aim of the present study was to investigate the role of P2X7R in atherosclerosis and the mechanisms of action of the NLRP3 inflammasome following stimulation with oxidized low-density lipoprotein (oxLDL). We observed the expression and distribution of P2X7R in the atherosclerotic plaque in the coronary arteries from an autopsy specimen and in that of the aortic sinuses of apoE(-/-) mice by immunohistochemistry and immunofluorescence staining. The specificity of short interfering RNA (siRNA) was used to suppress P2X7R and NLRP3 mRNA expression. RT-qPCR and western blot analysis were used to analyze mRNA and protein expression, respectively. Co-immunoprecipitation was used to examine the interaction between protein kinase R (PKR) phosphorylation and NLRP3. P2X7R and NLRP3 were expressed at high levels in the atherosclerotic plaque in the coronary arteries. Stimulation with oxLDL upregulated P2X7R, NLRP3 and interleukin (IL)-1 beta expression. P2X7R knockdown by siRNA suppressed NLRP3 inflammasome activation by inhibiting the PKR phosphorylation mediated by oxLDL. In the atherosclerotic lesions in the aortic sinuses of apoE-/- mice, P2X7R expression was found at high levels. Moreover, P2X7R siRNA attenuated the development of atherosclerosis in the apoE(-/-) mice. In conclusion, our results demonstrate that P2X7R plays a significant role in the development of atherosclerosis and regulates NLRP3 inflammasome activation by promoting PKR phosphorylation.
摘要：
Ten-eleven translocation-2 (TET2) protein is a DNA demethylase that regulates gene expression through DNA demethylation and also plays important roles in various diseases including atherosclerosis. Endothelial dysfunction represents an early key event in atherosclerotic disease. The cystathionine-gamma-lyase (CSE)/hydrogen sulfide (H2S) is a key endogenous system with protective effects on endothelial functions. In this study, we examined how TET2 regulates oxidized low-density lipoprotein (oxLDL)-induced dysfunction of human umbilical vein endothelial cells (HUVECs) and determined the role of the CSE/H2S system. Treatment with oxLDL resulted in downregulation of both TET2 expression and CSE/H2S system in HUVECs. TET2 was found to have protective effects on oxLDL-induced HUVEC dysfunction, which was confirmed with TET2 overexpression plasmid or TET2 shRNA plasmid. Moreover, TET2 was found to upregulate the CSE/H2S system and inhibit NF-kappa B activation, leading to decreased expression of ICAM-1 and VCAM-1 and attenuated adhesion of THP-1 cells to oxLDL-activated HUVECs. The protective effect of TET2 was reduced by treatment with CSE siRNA. Further studies revealed that CSE promoter region contains a well-defined CpG island. We also showed that TET2 enhanced 5-hydroxymethylcytosine (5hmC) level and promoted DNA demethylation of CSE gene promoter, leading to an increase in CSE expression. In conclusion, TET2 has protective effects on oxLDL-induced HUVEC dysfunction, likely through upregulating the CSE/H2S system by DNA demethylation of CSE gene promoter. TET2 may become a novel therapeutic target for endothelial dysfunction-associated vascular diseases.
作者机构：
[Wang, Zuo] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, PR China. Electronic address: smt121101@163.com;[Tang, Ya-ling; Li, Guo-hua; Zhao, Yue; Zhang, Kai; He, Xing-lan; Zhang, Hai; Peng, Juan; Wei, Dang-heng; Lin, Xiao-long; Li, Shuang; Ma, Xiao-feng; Wang, Ren; Lei, Jian-jun] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, PR China;[Zeng, Jun-fa] The Second Hospital Affiliated to University of South China, Hengyang, Hunan 421001, PR China;[Jiang, Zhi-Sheng] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, PR China. Electronic address: zsjianglab@yahoo.cn;[Zhang, Kai] The Second Hospital Affiliated to University of South China, Hengyang, Hunan 421001, PR China
通讯机构：
[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. Electronic address:
摘要：
Oxidised lipoprotein(a) [oxLp(a)] is considered as a more potent arteriosclerotic factor than native Lp(a). However, the molecular mechanisms underlying this potency remain unclear. Reactive oxygen species (ROS) possibly act as intracellular second messengers that participate in autophagy stimulation. In this study, the effect of oxLp(a) on endothelial cell autophagy was determined. The mechanism and effect of autophagy on endothelial cells were also investigated. Results showed that oxLp(a) could induce autophagy depending on the generation of cellular ROS. Superoxide dismutase, an antioxidant, could inhibit oxLp(a)-induced autophagy in human umbilical vascular endothelial cells. Furthermore, poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1)-liver kinase B1 (LKB1)-adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) and LKB1-AMPK-mTOR pathways are involved in oxLp(a)-induced autophagy. These pathways are also dependent on ROS. Thus, oxLp(a) induced autophagy via LKB1-AMPK-mTOR and PAPR-1-LKB1-AMPK-mTOR pathways, which are dependent on ROS generation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
期刊：
Journal of Long-Term Effects of Medical Implants,2013年23(4):339-357 ISSN：1050-6934
通讯作者：
Guidoin, R.(Robert.Guidoin@gmail.com)
作者机构：
[Robert Guidoin; Mark Nutley; Guy Dionne; Bin Li; Ze Zhang; Tieying Yin; Yvan Douville; Dangheng Wei; Nathalie Gilbert] Departments of Surgery and Radiology, Laval University and Quebec Biomaterials Institute, Ferdinand-Vandry Building, Quebec QC, G1V 0A6, Canada;[Gregory Samis; Mark Nutley] Division of Vascular Surgery, University of Calgary, Peter Laugheed Center, Calgary, AB, Canada;[rgen; Jutta Knifka] Institute of Anatomy, University Hospital of Cologne, Cologne, Germany;[Bin Li] Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China;[Jing Lin; Lu Wang] Key Laboratory of Textile Science and Technology, Ministry of Education, College of Textiles, Donghua University, Shanghai, China
摘要：
The aim of this study was to determine the molecular mechanism underlying the inhibition of vascular restenosis by Radix Sophorae Flavescentis (RSF) extract after balloon dilatation injury. In a rat carotid model of balloon dilatation injury, the RSF extract showed a significant inhibitory effect on vascular restenosis. Immunohistochemistry showed that the expression of tumor necrosis factor-alpha (TNF-alpha) in the vascular focus was markedly reduced upon treatment with the RSF extract, whereas the expression of proliferating cell nuclear antigens (PCNA) was mostly unaffected. Colorimetric assays of methylene blue incorporation demonstrated that the proliferation of cultured vascular smooth muscle cells (VSMCs) was not inhibited with serum from rats treated with RSF extract. However, the expression of TNF-alpha in cultured VSMCs was significantly downregulated by serum from rats treated with RSF extract. These results suggested that RSF extract has an inhibitory effect on vascular restenosis after balloon dilatation injury which might be, in part, attributable to its inhibition of TNF-alpha expression.
期刊：
Annals of biomedical engineering,2016年44(7):2218-2227 ISSN：0090-6964
通讯作者：
Peng, Zhao;Wang, Yu;Wei, Dangheng
作者机构：
[Li, Xiaohong; Jiang, Zhisheng; Wang, Zuo; Peng, Juan; Li, Rongqing; Yang, Qin; Wei, Dangheng] Institute of Cardiovascular Disease, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang;[Li, Xiaohong; Jiang, Zhisheng; Wang, Zuo; Peng, Juan; Li, Rongqing; Yang, Qin; Tang, Xiaoqing; Wei, Dangheng] 421001, China;[Peng, Zhao] Affiliated Hospital Xiang Nan University, Chengzhou;[Peng, Zhao] 423000, China;[Wang, Yu] Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
通讯机构：
[Wang, Yu] Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.;[Wei, Dangheng] Institute of Cardiovascular Disease, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, 421001, People's Republic of China.;[Peng, Zhao] Affiliated Hospital Xiang Nan University, Chengzhou, 423000, People's Republic of China.
摘要：
Low shear stress plays a crucial role in the initiation and progression of atherosclerotic lesions. However, the detailed mechanisms of these processes remain unclear. In this study, the effect of low shear stress on endothelial cell autophagy and its potential mechanism were investigated. Results showed autophagy dysfunction and ten-eleven translocation 2 (TET2) protein downregulation during atherosclerotic lesion progression. Autophagic markers BECLIN 1 and LC3II/LC3I under low shear stress (5 dyne/cm(2)) obviously decreased compared with those under physiological shear stress (15 dyne/cm(2)), whereas autophagic substrate p62 increased. TET2 expression was also downregulated under low shear stress. Endothelial cell autophagy was improved with TET2 overexpression but was impaired by TET2 siRNA treatment. Moreover, TET2 overexpression upregulated the expression of endothelial cell nitric oxide synthase (eNOS) and downregulated the expression of endothelin-1 (ET-1). TET2 siRNA further attenuated eNOS expression and stimulated ET-1 expression. Overall, the results showed that low shear stress downregulated endothelial cell autophagy by impaired TET2 expression, which might contribute to the atherogenic process.
摘要：
Tet methylcytosine dioxygenase 2 (TET2) mediates the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The loss of TET2 is associated with advanced atherosclerotic lesions. Our previous study showed that TET2 improves endothelial cell function by enhancing endothelial cell autophagy. Accordingly, this study determined the role of TET2 in atherosclerosis and potential mechanisms. In ApoE-/- mice fed high-fat diet, TET2 overexpression markedly decreased atherosclerotic lesions with uniformly increased level of 5hmC and decreased level of 5mC in genomic DNA. TET2 overexpression also promoted autophagy and downregulated inflammation factors, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, monocyte chemotactic protein 1, and interleukin-1. Consistently, TET2 knockdown with small hairpin RNA (shRNA) in ApoE-/- mice decreased 5hmC and increased 5mC levels in atherosclerotic lesions. Meanwhile, autophagy was inhibited and atherosclerotic lesions progressed with an unstable lesion phenotype characterized by large lipid core, macrophage accumulation, and upregulated inflammation factor expression. Experiments with the cultured endothelial cells revealed that oxidized low-density lipoprotein (ox-LDL) inhibited endothelial cell autophagy. TET2 shRNA strengthened impaired autophagy and autophagic flux in the ox-LDL-treated endothelial cells. TET2 overexpression reversed these effects by decreasing the methylation level of the Beclin 1 promoter, which contributed to the downregulation of inflammation factors. Overall, we identified that TET2 was downregulated during the pathogenesis of atherosclerosis. The downregulation of TET2 promotes the methylation of the Beclin 1 promoter, leading to endothelial cell autophagy, impaired autophagic flux, and inflammatory factor upregulation. Upregulation of TET2 may be a novel therapeutic strategy for treating atherosclerosis.
摘要：
Proprotein convertase subtilisin/kexin 9 (PCSK9), a member of the protein-converting enzyme family, is highly expressed in adult hepatocytes and small intestinal enterocytes. To our knowledge, in this study, we demonstrate for the first time that PCSK9 is upregulated in a dose-dependent manner via oxidized low-density lipoprotein (oxLDL) stimulation in THP-1-derived macrophages. PCSK9 small interfering RNA (siRNA) suppresses the oxLDL-induced inflammatory cytokine expression in THP-1-derived macrophages. The exposure of macrophages to oxLDL markedly increased the expression of NF-kappa B protein in the nucleus. However, this effect was significantly attenuated by PCSK9 si RNA. These findings indicate that PCSK9 expression is induced by ox LDL, and that PCSK9 si RNA protects against inflammation via the inhibition of NF-kappa B activation in oxLDL-stimulated THP-1-derived macrophages. Our results suggest that PCSK9 may be used as a therapeutic target for the treatment of atherosclerosis since PCSK9 siRNA suppresses oxLDL-induced I kappa B-alpha degradation and NF-kappa B nuclear translocation into THP-1-derived macrophages.
