摘要：
Atherosclerosis (AS) is a chronic inflammatory disease accompanied by complex pathological changes, such as endothelial dysfunction, foam cell formation, and vascular smooth muscle cell proliferation. Many approaches, including regulating AS-related gene expression in the transcriptional or post-transcriptional level, contribute to alleviating AS development. The DNA methylation is a crucial epigenetic modification in regulating cell function by silencing the relative gene expression. The microRNA (miRNA) is a type of noncoding RNA that plays an important role in gene post-transcriptional regulation and disease development. The DNA methylation and the miRNA are important epigenetic factors in AS. However, recent studies have found a mutual regulation between these two factors in AS development. In this study, recent insights into the roles of miRNA and DNA methylation and their interaction in the AS progression are reviewed.
期刊：
JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH,2020年46(9):1690-1701 ISSN：1341-8076
通讯作者：
Meng, Jun;Wu, ShiYuan;Wang, Zuo
作者机构：
[Zeng, Jun-Fa; Tao, Jun; Xia, Lin-Zhen; Chen, Jiao-Jiao; Wang, Zuo] Univ South China, Key Lab Arteriosclerol Hunan Prov, Hunan Int Sci & Technol Cooperat Base Arterioscle, Inst Cardiovasc Dis,Hengyang Med Coll, Hengyang, Peoples R China.;[Meng, Jun] Univ South China, Funct Dept, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;[Wu, ShiYuan] YueYang Maternal Child Med Hlth Hosp, Hunan Prov Innovat Training Base Med Postgrad, Yueyang 416000, Hunan, Peoples R China.;[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：
[Meng, Jun; Wang, Zuo] U;[Wu, ShiYuan] Y;Univ South China, Funct Dept, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;YueYang Maternal Child Med Hlth Hosp, Hunan Prov Innovat Training Base Med Postgrad, Yueyang 416000, 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：
gestational diabetes mellitus;HTR8-S/Vneo;placental growth factor;pre-eclampsia;reactive oxygen species
摘要：
Fibroblast growth factor 21 (FGF21) acts as an anti-atherosclerotic agent. However, the specific mechanisms governing this regulatory activity are unclear. Autophagy is a highly conserved cell stress response which regulates atherosclerosis (AS) by reducing lipid droplet degradation in foam cells. We sought to assess whether FGF21 could inhibit AS by regulating cholesterol metabolism in foam cells via autophagy and to elucidate the underlying molecular mechanisms. In this study, ApoE(-/-) mice were fed a high-fat diet (HFD) with or without FGF21 and FGF21 + 3-Methyladenine (3MA) for 12 weeks. Our results showed that FGF21 inhibited AS in HFD-fed ApoE(-/-) mice, which was reversed by 3MA treatment. Moreover, FGF21 increased plaque RACK1 and autophagy-related protein (LC3 and beclin-1) expression in ApoE(-/-) mice, thus preventing AS. However, these proteins were inhibited by LV-RACK1 shRNA injection. Foam cell development is a crucial determinant of AS, and cholesterol efflux from foam cells represents an important defensive measure of AS. In this study, foam cells were treated with FGF21 for 24 hours after a pre-treatment with 3MA, ATG5 siRNA or RACK1 siRNA. Our results indicated that FGF21-induced autophagy promoted cholesterol efflux to reduce cholesterol accumulation in foam cells by up-regulating RACK1 expression. Interestingly, immunoprecipitation results showed that RACK1 was able to activate AMPK and interact with ATG5. Taken together, our results indicated that FGF21 induces autophagy to promote cholesterol efflux and reduce cholesterol accumulation in foam cells through RACK1-mediated AMPK activation and ATG5 interaction. These results provided new insights into the molecular mechanisms of FGF21 in the treatment of AS.
摘要：
The therapeutic effect of metformin (Met) on atherosclerosis was studied here. Effects of methionine and Met on the induction of inflammatory response and H2S expression in peritoneal macrophages were evaluated. Enzyme-linked immunosorbent assay, immunohistochemistry assay, western blot, and quantitative reverse transcription polymerase chain reaction were conducted to observe the levels of cystathionine gamma-lyase (CSE), DNA methyltransferases 1 (DNMT1), DNMT3a, DNMT3b, tumor necrosis factor (TNF- alpha), interleukin 1b (IL-1 beta), and hydrogen sulfide (H2S). Luciferase and bisulfite sequencing assays were also utilized to evaluate the CSE promoter activity as well as the methylation status of CSE in transfected cells. Methionine significantly elevated Hcy, TNF-a, H2S, and IL-1 beta expression while decreasing the level of CSE in C57BL/6 mice. In contrary, co-treatment with Methionine and Met reduced the detrimental effect of Methionine. Homocysteine (Hcy) decreased H2S expression while promoting the synthesis of IL-1 beta and TNF-alpha in THP-1 and raw264.7 cells. Treatment of THP-1 and raw264.7 cells with methionine and Met reduced the activity of methionine in dose dependently. Moreover, Hcy increased the expression of DNMT and elevated the level of methylation in the CSE promoter, whereas the co-treatment with methionine and Met attenuated the effects of Hcy. Methionine significantly decreased plasma level of CSE while increasing the severity of inflammatory responses and plasma level of Hcy, which in turn suppressed H2S synthesis and enhanced DNA hypermethylation of CSE promoter to promote the pathogenesis of atherosclerosis. In contrary, co-treatment with methionine and Met reduced the detrimental effect of methionine.
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：
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.
期刊：
Lipids in Health and Disease,2017年16(1):1-10 ISSN：1476-511X
通讯作者：
Wang, Zuo;Zhang, Hai
作者机构：
[Ma, Xiaofeng] Univ South China, Dept Cardiol, Affiliated Nanhua Hosp, Hengyang 421001, Peoples R China.;[Qu, Kai; Ma, Xiaofeng; Liu, Yami; Wang, Zuo] Univ South China, Inst Cardiovasc Dis, Key Lab Atherosclerol Human Prov, Hengyang 421001, Peoples R China.;[Tan, Yanmei] Changde Vocat Tech Coll, Dept Pathol, Changde 415000, Peoples R China.;[He, Xinglan] Women & Children Healthcare Hosp Zhu Zhou, Zhuzhou 412000, Peoples R China.;[Zhang, Hai] Univ South China, Dept Pathol, Affiliated Hosp 1, Hengyang 421001, Peoples R China.
通讯机构：
[Wang, Zuo; Zhang, Hai] U;Univ South China, Inst Cardiovasc Dis, Key Lab Atherosclerol Human Prov, Hengyang 421001, Peoples R China.;Univ South China, Dept Pathol, Affiliated Hosp 1, Hengyang 421001, Peoples R China.
关键词：
Lipoprotein(a);Apolipoprotein(a);Diallyl disulfide;Extracellular regulated protein kinases;Mitogen-activated protein kinases;HepG2 cell
摘要：
Lipoprotein(a) [LP(a)] is implicated as a common and independent risk factor for cardiovascular diseases. The therapeutic options currently available for reducing plasma LP(a) concentrations are limited. Diallyl disulphide (DADS), the main component of garlic, regulates lipid metabolism in hepatocytes and adipocytes through ERK1/2 signalling. This study aimed to assess the effect of DADS on apolipoprotein(a) [apo(a)] in HepG2 cells. We also determined the effects of DADS on apo(a) expression and secretion in HepG2 cells as well as the underlying mechanisms. We examined the role of DADS on apo(a) expression in HepG2 cells by treating cell with different concentrations of DADS (10, 20, 40 and 80 μg/mL) for 24 h or treating cells with 40 μg/mL DADS for 0, 6, 12, 24 and 48 h. Then we used quantitative real-time PCR to analysis apo(a) mRNA levels, used Western blot to analysis apo(a) protein levels and used enzyme-linked immunosorbent assay to test apo(a) secreted levels. To farther determined the role of DADS, we applied Transfection of small interfering RNA to knockdown ELK-1levels and applied PD98059, a specific inhibitor of ERK1/2, to block ERK1/2 signal. The results show DADS inhibited apo(a) at both the mRNA and protein levels in HepG2 cells in a dose-dependent manner. DADS-mediated inhibition of apoa(a) expression in HepG2 cells was attenuated when the cells were cultured in medium containing PD98059 (ERK1/2 inhibitor) or were transfected with siRNAs against MEK1 or ELK-1. Overexpression of apo(a) yielded similar results. This study reveals that DADS can downregulate apo(a) expression in a dose-dependent manner via the MEK-ERK12-ELK-1 pathway.
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.
摘要：
Chemotherapy is the most common therapeutic strategy for the treatment of unresectable hepatocellular carcinoma. However, the therapeutic efficacy is limited by the low delivery efficiency of chemotherapeutics and severe toxicity towards healthy tissues. To address these challenges, active-targeting mesoporous silica nanoparticles conjugating a platinum(IV) prodrug were developed as a therapy for liver cancer for the first time. Taking advantage of liver-targeting lactobionic acid (LA), the smart nano-carriers not only enhanced the circulation time, but also effectively concentrated at the liver tumor site. Moreover, the conjugated platinum(IV) could be reduced in the reductive tumor environment for the fast release of active platinum(II). The novel targeting and self-responsive drug-loading system offers new prospects for liver cancer chemotherapy.
摘要：
Atherosclerotic lesions are characterized by the accumulation of abundant lipids and chronic inflammation. Previous researches have indicated that macrophage-derived lipoprotein lipase (LPL) promotes atherosclerosis progression by accelerating lipid accumulation and proinflammatory cytokine secretion. Although apelin-13 has been regarded as an atheroprotective factor, it remains unclear whether it can regulate the expression of LPL. The aim of this study was to explore the effects of apelin-13 on the expression of LPL and the underlying mechanism in THP-1 macrophage-derived foam cells. Apelin-13 significantly decreased cellular levels of total cholesterol, free cholesterol, and cholesterol ester at the concentrations of 10 and 100 nM. ELISA analysis confirmed that treatment with apelin-13 reduced pro-inflammatory cytokine secretion, such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). It was also found that apelin-13 inhibited the expression of LPL as revealed by western blot and real-time PCR analyses. Bioinformatics analyses and dual-luciferase reporter assay indicated that miR-361-5p directly downregulated the expression of LPL by targeting the 3'UTR of LPL. In addition, apelin-13 + miR-361-5p mimic significantly downregulated the expression of LPL in cells. Finally, we demonstrated that apelin-13 downregulated the expression of LPL through activating the activity of PKCa. Taken together, our results showed that apelin-13 downregulated the expression of LPL via activating the APJ/PKCa/miR-361 -5p signaling pathway in THP-1 macrophage-derived foam cells, leading to inhibition of lipid accumulation and proinflammatory cytokine secretion. Therefore, our studies provide important new insight into the inhibition of lipid accumulation and pro-inflammatory cytokine secretion by apelin-13, and high-light appelin-13 as a promising therapeutic target in atherosclerosis.
