摘要：
Atherosclerotic cardiovascular disease is the major cause of death worldwide. Low shear stress plays key roles on the initiation and progression of atherosclerosis (As). However, its underlying mechanism remains unclear. In this study, the effect of low shear stress on endothelial mesenchymal transformation (EndMT) and its underlying mechanism were explored. Results showed that in cultured human umbilical vein endothelial cells, low shear stress down-regulated the expression of TET2 and promoted EndMT. Loss of TET2 promoted EndMT with the Wnt/beta-catenin signaling pathway. The enhancement in EndMT induced by low shear stress was attenuated by TET2 overexpression. In apoE(-/-) mice subjected to carotid artery local ligation, the EndMT and atherosclerotic lesions induced by low shear stress was attenuated by TET2 overexpression. Taken together, low shear stress promoted EndMT through the down-regulation of TET2, indicating that intervention with EndMT or the up-regulation of TET2 might be an alternative strategy for preventing As. (C) 2021 Elsevier Inc. All rights reserved.
摘要：
Vascular endothelial cell (VEC) inflammation induced by low shear stress plays key roles in the initiation and progression of atherosclerosis (As). Pyroptosis is a form of inflammatory programmed cell death that is critical for As. However, the effect of low shear stress on VEC pyroptosis and the underlying mechanisms were not clear. Here we show that low shear stress promoted VEC pyroptosis and reduced the expression of Ten-Eleven Translocation 2 (TET2) methylcytosine dioxygenase. Loss of TET2 resulted in the upregulation of the expression and activity of mitochondrial respiratory complex II subunit succinate dehydrogenase B (SDHB) by decreasing the recruitment of histone deacetylase 2, independent of DNA demethylation modification. The overexpression of SDHB mediated mitochondrial injury and increased the production of reactive oxygen species (ROS). The administration of ROS scavenger NAC alleviated VEC pyroptosis induced by SDHB overexpression and TET2 shRNA. These findings show that low shear stress induced endothelial cell pyroptosis through the TET2/SDHB/ROS pathway and offer new insights into As.
期刊：
DNA AND CELL BIOLOGY,2020年39(4):661-670 ISSN：1044-5498
通讯作者：
Lv, Yun-Cheng;Li, Guo-Hua;Wang, Zuo
作者机构：
[Zeng, Jun-Fa; Li, Guo-Hua; Tao, Jun; Wei, Dang-Heng; Chen, Jiao-Jiao; Xia, Lin-Zhen; Zhang, Hai; Wang, Zuo] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov,Hengyang Med Co, Hunan Int Sci & Technol Cooperat Base Arterioscle, Hengyang, Hunan, Peoples R China.;[Zhang, Xiao-Lei] Jiangsu Coll Nursing, Huaian, Jiangsu, Peoples R China.;[Lv, Yun-Cheng] Univ South China, Clin Anat & Reprod Med Applicat Inst, Hengyang City 421001, Hunan, Peoples R China.;[Li, GH; Wang, Zuo] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, Heng Yang Med Sch, Hengyang City 421001, Peoples R China.
通讯机构：
[Lv, Yun-Cheng; Li, GH; Wang, Z] U;Univ South China, Clin Anat & Reprod Med Applicat Inst, Hengyang City 421001, Hunan, Peoples R China.;Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, Heng Yang Med Sch, Hengyang City 421001, Peoples R China.
关键词：
Tet methylcytosine dioxygenase 2;atherosclerosis;fibroblast growth factor 21;human umbilical vein endothelial cells;pyroptosis;reactive oxygen species;ubiquinol cytochrome c reductase core protein I
摘要：
INTRODUCTION: MiR-124-3p is one of the aberrantly expressed miRNAs in the placentas of patients with preeclampsia (PE), a severe obstetric complication characterised by hypertension and proteinuria. This study aimed to investigate the role of miR-124-3p in the invasion, migration and death of trophoblast cells and explore the potential mechanisms. METHODS: MiR-124-3p expression in placental tissues was compared with that in normal placenta. HTR8/SVneo cells were then transfected with miR-124-3p mimics to examine cellular apoptosis, migration and invasion. Furthermore, the expression of pyroptosis-related molecular NLRP3, Pro-caspase1, caspase1, IL-1β and GSDMD was examined with Western blot. Dual luciferase reporter assay was performed to confirm that placental growth factor (PLGF) is a direct target of miR-124-3p, and HTR-8/SVneo cells were transfected with small interfering RNA PLGF (siPLGF) to determine whether PLGF knockdown promotes HTR-8/SVneo pyroptosis. Finally, intracellular ROS was diminished with N-acetyl-l-cysteine (NAC) to observe whether the pro-pyroptosis effect of PLGF knockdown is alleviated. RESULTS: Results in this study showed that miR-124-3p expression was remarkably increased in the placenta of patients with PE. Moreover, the transfection of miR-124-3p mimics in trophoblastic cells significantly decreased cell migration and invasion but increased cell apoptosis and the expression of NLRP3, pro-caspase1, caspase1, IL-1β and GSDMD. Therefore, PLGF was confirmed as a direct target of miR-124-3p. Finally, siPLGF transfection can mimic the effects of miR-124-3p, and NAC can inhibit this effect. CONCLUSION: In summary, miR-124-3p is upregulated in PE, and in vitro functional analysis revealed that this mRNA inhibits trophoblast invasion and migration but promotes cell pyroptosis partly via the PLGF-ROS pathway.
摘要：
Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.
期刊：
JOURNAL OF CELLULAR PHYSIOLOGY,2020年235(10):6582-6591 ISSN：0021-9541
通讯作者：
Wang, Zuo;Wei, DangHeng;Yin, WeiDong
作者机构：
[Chen, JinNa; Chen, JiaoJiao; Tao, Jun; Yin, WeiDong; Wei, DangHeng; Wu, Peng; Wang, Zuo] Univ South China, Hunan Int Sci & Technol Cooperat Base Arterioscle, Hunan Prov Innovat Training Base Med Postgrad, Inst Cardiovasc Dis,Key Lab Arteriosclerol Hunan, Hengyang, Hunan, Peoples R China.;[Chen, JinNa; Chen, JiaoJiao; Tao, Jun; Yin, WeiDong; Wei, DangHeng; Wu, Peng; Wang, Zuo] Univ South China, Yueyang Woman & Childrens Med Ctr, Hengyang Med Coll, Hengyang, Hunan, Peoples R China.;[Xu, GaoSheng; Wu, ShiYuan; Wu, Peng] Hunan YueYang Maternal & Child Med Health Care Ho, Hunan Prov Innovat Training Base Med Postgrad, Yueyang, Hunan, Peoples R China.;[Wang, Zuo; Wei, DangHeng; Yin, WeiDong] Univ South China, Hengyang 42001, Hunan, Peoples R China.
通讯机构：
[Wang, Z; Wei, DH; Yin, WD] U;Univ South China, Hengyang 42001, Hunan, Peoples R China.
关键词：
atherosclerosis;pyroptosis;ROS;SDHB;TMAO
摘要：
<jats:title>Abstract</jats:title><jats:p>Trimethylamine N‐oxide (TMAO) is produced from the phosphatidylcholine metabolism of gut flora and acts as a risk factor of cardiovascular disease. However, the underlying mechanisms for its proatherogenic action remain unclear. This study aimed to observe the effect of TMAO on endothelial cell pyroptosis and explore the underlying mechanisms. Our results showed that TMAO promoted the progression of atherosclerotic lesions in apolipoprotein E‐deficient (apoE<jats:sup>−/−</jats:sup>) mice fed a high‐fat diet. Pyroptosis and succinate dehydrogenase complex subunit B (SDHB) upregulation were detected in the vascular endothelial cells of apoE<jats:sup>−/−</jats:sup> mice and in cultured human umbilical vein endothelial cells (HUVECs) treated with TMAO. Overexpression of SDHB in HUVECs enhanced pyroptosis and impaired mitochondria and high reactive oxygen species (ROS) level. Pyroptosis in the SDHB overexpression of endothelial cells was inhibited by the ROS scavenger NAC. In summary, TMAO promotes vascular endothelial cell pyroptosis via ROS induced through SDHB upregulation, thereby contributing to the progression of atherosclerotic lesions.</jats:p>
摘要：
Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.
作者机构：
[Jiang, Zhi-Sheng; Hao, Ya-Meng; Ren, Zhong; Qu, Shun-Lin; Yin, Kai; Yuan, Hou-Qin; Wei, Dang-Heng; Liu, Lu-Shan] Univ South, Key Lab Arteriosclerosis Hunan Prov, Inst Cardiovasc Dis, Hengyang City 421001, Hunan, Peoples R China.;[Yin, Kai] Univ South China, Med Sch, Res Lab Translat Med, Hengyang 421001, Peoples R China.;[Fu, Mingui] Univ Missouri, Sch Med, Shock Trauma Res Ctr, Dept Biomed Sci, Kansas City, MO 64108 USA.;[Jiang, Zhi-Sheng] Univ South China, Key Lab Arteriosclerol Hunan Prov, Inst Cardiovasc Dis, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Jiang, Zhi-Sheng] U;Univ South China, Key Lab Arteriosclerol Hunan Prov, Inst Cardiovasc Dis, Hengyang 421001, Hunan, Peoples R China.
关键词：
Atherosclerosis;Endothelial cell;Endothelial to mesenchymal transition;Vascular remodeling
摘要：
Endothelial cells are the main components of the heart, blood vessels, and lymphatic vessels, which play an important role in regulating the physiological functions of the cardiovascular system. Endothelial dysfunction is involved in a variety of acute and chronic cardiovascular diseases. As a special type of epithelial-mesenchymal transition (EMT), endothelium to mesenchymal transition (EndMT) regulates the transformation of endothelial cells into mesenchymal cells accompanied by changes in the expression of various transcription factors and cytokines, which is closely related to vascular endothelial injury, vascular remodeling, myocardial fibrosis and valvar disease. Endothelial cells undergoing EndMT lose their endothelial characteristics and undergo a transition toward a more mesenchymal-like phenotype. However, the molecular mechanism of EndMT remains unclear. EndMT, as a type of endothelial dysfunction, can cause vascular remodeling which is a major determinant of atherosclerotic luminal area. Therefore, exploring the important signaling pathways in the process of EndMT may provide novel therapeutic strategies for treating atherosclerotic diseases.
摘要：
Mitochondria are highly dynamic organelles beyond powerhouses of a cell. These components also play important roles in cell homeostasis by regulating cell function and phenotypic modulation. Atherosclerosis is the leading cause of morbidity and mortality in developed and developing countries. Mitochondrial dysfunction has been increasingly associated with the initiation and progression of atherosclerosis by elevating the production of reactive oxygen species and mitochondrial oxidative stress damage, mitochondrial dynamics dysfunction, and energy supply. In this review, we describe the progression of the link between mitochondrial dysfunction and atherosclerosis and its potential regulation mechanisms.
摘要：
<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>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.</jats:p></jats:sec>
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.
