MPO的氧化能力与涉及Cys残基错义突变的APOE基因多态性的交互作用与高血压严重程度的关联和机制研究

项目来源

国家自然科学基金(NSFC)

项目主持人

刘雅文

项目受资助机构

吉林大学

项目编号

81973120

立项年度

2019

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

55.00万元

学科

医学科学-预防医学-非传染病流行病学

学科代码

H-H30-H3010

基金类别

面上项目

关键词

交互作用 ; 载脂蛋白E ; 髓过氧化物酶 ; 高血压 ; 基因多态性 ;

参与者

乔乙春;谷雨璐;刘思宇;李勇;刘云恺;史记康;任亚璇;邱爽;赵倩

参与机构

未公开

项目标书摘要:微血管结构和功能改变是阻碍血流流速、形成高血压的主要原因。MPO和apoE是HDL和LDL结合的蛋白。HDL和LDL从血浆跨过内皮进入外周微血管的细胞间液,导致MPO和apoE与微血管细胞相互作用。MPO的氧化作用改变微血管结构和功能,MPO水平增加与舒张压正关联,MPO水平降低与血压降低相关。涉及Cys残基错义突变的APOE基因多态性决定不同个体apoE抗氧化能力强弱,但是不同个体apoE被氧化状态由MPO氧化能力决定。我们前期研究发现:高血压合并动脉粥样硬化患者血清MPO过氧化体系与LDL的活性醛基渐进性修饰增强相关;APOE基因中突变成无抗氧化能力氨基酸残基的基因多态性位点可能是高血压的危险因素。基于MPO的氧化能力与apoE的抗氧化能力的直接对抗关系,本项目旨在研究HDL和LDL所结合MPO的氧化能力与涉及Cys残基错义突变的APOE基因多态性的交互作用与高血压严重程度的关联和机制

Application Abstract: Myeloperoxidase(MPO)and apolipoprotein E(apoE)are high-density-lipoprotein-binding and low-density-lipoprotein-binding proteins.LDL and HDL transfer from plasma into interstitial fluid across the peripheral vascular endothelium via passive ultrafiltration in humans,reflecting that MPO and apoE interact with microvascular cells.MPO oxidation leads to the changes in microvascular structure and function,conferring hypertension process.Notably,there are two cysteine(Cys)-correlating missense mutations in APOE polymorphisms(rs429358 and rs7412).Cys is susceptible to oxidation to give the disulfide derivative cystine,serving as an important structural and anti-oxidative role.ApoE restricts MPO oxidation,and there are differences in the antioxidant capacity and oxidized state of apoE in different individuals.Our previous investigations indicated that ⑴ the shift from the reaction system of paraoxonase 1 to the peroxidation reaction system of MPO correlates with atherosclerosis;⑵ the peroxidation reaction system of MPO correlated with progressive LDL modifications via reactive aldehydes in atherosclerotic patients with hypertension;and ⑶ APOE genotypes(ε2/ε2 and ε2/ε3)showed a possible association with hypertension,and APOE genotypes(ε3/ε4 and ε4/ε4)had a 2.08-fold risk of developing hypertension.Based on substantial confrontation between MPO oxidation and apoE anti-oxidation,we shall investigate the contribution of interactions between the oxidative capacity of MPO and APOE polymorphism involved in cysteine-missense mutations to the severity of hypertension.

项目受资助省

吉林省

项目结题报告(全文)

微血管结构和功能改变是阻碍血流流速、形成高血压的主要原因。APOE基因中突变成无抗氧化能力氨基酸残基的基因多态性位点可能是高血压的危险因素。我前期发现:ApoE基因型(ε3/ε4和ε4/ε4)可能是高血压的危险因素。由于Cys残基数量的差别,从apoE2、apoE3到apoE4,呈现出明显下降的抗氧化能力,可见apoE2、apoE3和apoE4的功能存在差异。由于apoE无法穿透内皮细胞膜,我们推测apoE与内皮损伤之间可能存在可以穿过内皮细胞膜的中介分子。在本项目的资助下,我们发现miR-3656是apoE2、apoE3和apoE4富集的miR之一,富集程度差异明显,miR-3656是apoE4所致血管内皮损伤差异的中介分子:miR-3656通过靶向eNOS和ADAMTS13诱导血管内皮细胞损伤;miR-3656驱动的KLF10表达抑制是高血压内皮功能障碍的关键机制环节。我们进一步研究eNOS基因多态性与高血压的关系,发现eNOS rs1799983多态性与高血压风险增加相关。我们进行了长春地区高血压流行病学调查研究工作,发现长春市高血压的知晓率、治疗率和控制率均高于中国,说明长春市高血压防治工作是有效的。然而,中国老年人群中高血压的患病率低于长春,这也使得长春对高血压的监管面临巨大挑战。我们研究了老年人高血压前期或高血压向糖尿病发展的发病率及危险因素,发现与高血压前期参与者相比,高血压患者患糖尿病的风险较高。抗高血压药物与高血压患者从非糖尿病到糖尿病的趋势降低有关。同时,我们也研究了老成年居民多发病的社会地理和行为影响,发现高血压家族史和糖尿病家族史与高并发症风险显着相关。

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  • 1.Association of total and regional fat-to-muscle ratio with the risk of metabolic dysfunction-associated fatty liver disease and other chronic liver diseases.

    • 关键词:
    • Body composition; Cirrhosis; Fat-to-muscle ratio; HCC; Liver-related mortality; MASLD; PDFF; Prospective cohort study; UK Biobank; cT1
    • Xi, Yingao;Liang, Zhuoshuai;Jin, Huizhen;Jiang, Yawen;Tan, Ran;Zhang, Yuan;Wang, Jiahe;Sui, Wenjing;Liu, Binyu;Zhang, Hongrui;Li, Xiaoyang;Li, Yong;Liu, Yunkai;Cheng, Yi;Liu, Yawen
    • 《Hepatology international》
    • 2026年
    • 期刊

    BACKGROUND: We examined whether total and regional fat-to-muscle ratio (FMR) predicts incident metabolic dysfunction-associated steatotic liver disease (MASLD) and other chronic liver outcomes.; METHODS: Among 356,833 UK Biobank participants (men: 168,784 [47.3%]; women: 188,049 [52.7%]; mean age 56.3years), body composition was assessed by segmental bioelectrical impedance analysis (BIA), from which whole-body and regional (arm, leg, trunk) FMRs were derived and categorized into sex-specific tertiles. Tertile cutpoints (lower and upper) were: men-whole-body (0.309, 0.396), arm (0.264, 0.333), leg (0.254, 0.325), trunk (0.348, 0.453); women-whole-body (0.526, 0.679), arm (0.500, 0.692), leg (0.640, 0.778), trunk (0.462, 0.621). Cox proportional hazards models were applied. MRI subsets included liver proton density fat fraction (PDFF) (n=32,191) and hepatic fibro-inflammation (iron-corrected T1 [cT1]) (n=27,028).; RESULTS: Over a median follow-up of 14.0years, there were 4,404 MASLD, 1,392 cirrhosis, 947 liver-related mortality, and 147 HCC events. Comparing the highest (T3) versus the lowest (T1) tertile of FMR, MASLD risk increased in both sexes across whole-body and regional FMRs (HR 2.29-2.76), with the strongest associations for leg FMR in women (HR 2.95). For cirrhosis and liver-related mortality, T3 associations were mainly seen in men and were strongest for whole-body and trunk/arm FMR (HR 1.63-2.11), while women showed weak/null associations (HR 1.29-1.54). For HCC, T3 FMR was strongly associated in men (HR 3.03-4.71), while no clear associations were evident in women.; CONCLUSION: Higher total and regional FMR predicts MASLD and advanced liver outcomes with clear sex- and region-specific patterns. © 2026. The Author(s), under exclusive licence to Asian Pacific Association for the Study of the Liver.

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  • 2.Association between heavy metals and risk of cardiovascular diseases in US adults with prediabetes from NHANES 2011-2018.

    • 关键词:
    • 0 / Metals, Heavy. 00BH33GNGH / Cadmium. 2P299V784P / Lead;Cardiovascular disease; Environmental exposure; Plasma metals; Prediabetes
    • Yang, Sijia;Liang, Zhuoshuai;Qiu, Yue;Li, Xiaoyang;Tian, Yuyang;Liu, Yawen
    • 《BMC public health》
    • 2025年
    • 25卷
    • 1期
    • 期刊

    BACKGROUND: The association of plasma metals on the risk of cardiovascular diseases (CVD) in adults with prediabetes remains poorly investigated. To assess the association between plasma metal exposure and the risk of CVD in prediabetic adults in the United States using five plasma metals.; METHODS: Five cycles of data (2011-2012, 2013-2014, 2015-2016, and 2017-2018) from the NHANES were adopted in this study. The plasma metals were measured in 1088 participants with prediabetes. We utilized multivariate logistic regression, WQS, and BKMR models to evaluate the associations between the five plasma metals and the risk of CVD.; RESULTS: The risk of CVD in participants with prediabetes were found to link to the 2nd quartile, 3rd and 4th quartiles of cadmium on the basis of multivariate logistic model (OR=3.03, 95%CI: 1.17-7.82, P<0.01). Moreover, the joint effect of the five metals on the risk of CVD participants with prediabetes were unveiled using WQS and BKMR models (OR=1.79, 95%CI: 1.15-2.77, P<0.01). In addition, when the concentrations of the other four metals were controlled at the 25th, 50th, and 75th percentile, correspondingly, cadmium had a statistically significant positive association with the risk of CVD.; CONCLUSION: The exposure of metals documented by the five metals links to the risk of CVD in participants with prediabetes in the United States. Among all the five metals, cadmium has the strongest association with the risk of CVD in participants with prediabetes. © 2025. The Author(s).

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  • 3.Association between glyphosate exposure and osteoarthritis in US adults: Especially in people who are obese and inactive in leisure time physical activity

    • 关键词:
    • Herbicides;Body mass;Body mass index;Confidence interval;Glyphosates;Leisure time;Leisure time physical activity;Mass index;Moderating effect;Osteoarthritis;Physical activity
    • Liang, Zhuoshuai;Sun, Xiaoyue;Guo, Ruifang;Wang, Hongwei;Tian, Yuyang;Wang, Yujian;Liu, Yawen;Liu, Siyu
    • 《Science of the Total Environment》
    • 2024年
    • 927卷
    • 期刊

    Objective: Little has been known on the effect of chronic glyphosate exposure on osteoarthritis (OA). The aim of this study was to investigate the association between glyphosate exposure and OA and to further investigate the different moderating effects of leisure time physical activity (LTPA) and body mass index (BMI) types on the association between glyphosate exposure and OA. Methods: Cross-sectional data from 2540 participants in the 2015–2018 National Health and Nutrition Examination Survey (NHANES) were used to explore the association between glyphosate exposure and OA. Multivariate logistic regression models and restricted cubic spline models were used to investigate the association between glyphosate exposure and OA, and further analyses were conducted to determine the association between glyphosate exposure and OA under different LTPA and BMI types. Results: Of the 2540 participants, 346 had OA. Participants with the highest glyphosate concentration (Q4) had a higher incidence of OA compared to participants with the lowest glyphosate concentration (Q1) (OR, 1.88; 95 % confidence interval [CI]: 1.13, 3.13), there was no nonlinear association between glyphosate and OA (non-linear P = 0.343). In the no LTPA group, glyphosate concentration in the Q4 group was correlated with OA (OR, 2.65; 95%CI: 1.27, 5.51). In the obese group, glyphosate concentration in the Q4 group was correlated with OA (OR, 2.74; 95 % CI: 1.48, 5.07). Among people with high BMI and inactive in LTPA, glyphosate concentrations in Q4 were associated with OA (OR, 2.19; 95 % CI: 1.07, 4.48). Conclusions: Glyphosate is associated with OA odd, and physical activity and moderate weight loss can mitigate this association to some degree. This study provides a scientific basis for rational prevention of OA by regulation of LTPA and BMI under glyphosate exposure. © 2024 Elsevier B.V.

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  • 4.Association of the live microbe intake from foods with all-cause and cardiovascular disease-specific mortality: a prospective cohort study.

    • 关键词:
    • Health promotion; Live dietary microbes; Mortality; Population-attributable fractions; Prospective study
    • Liang, Zhuoshuai;Sun, Xiaoyue;Shi, Jikang;Tian, Yuyang;Wang, Yujian;Cheng, Yi;Liu, Yawen
    • 《European journal of nutrition》
    • 2024年
    • 期刊

    BACKGROUND: Live dietary microbes have been hypothesized to promoting human health. However, there has been lacking perceptions to crystallize nexus between consumption of foods with live microbes and mortality.; OBJECTIVE: To investigate the association of consumption of foods with medium to high amounts of live microbes with all-cause, cancer-specific, and cardiovascular disease (CVD)-specific mortality.; METHODS: The data were obtained from the National Health and Nutrition Examination Survey 1999-2018 at baseline linked to the 2019 National Death Index records. Based on consumption of foods that were categorized as either having medium or high microbial content (MedHi foods), participants were classified into three groups. Kaplan-Meier survival curves and multivariable Cox regression models were used to estimate the association of consumption of MedHi foods with mortality. Population-attributable fractions (PAFs) of consumption of MedHi foods in relation to mortality risk were also estimated.; RESULTS: A total of 35,299 adults aged≥20 years were included in this study. During a median follow-up of 9.67 years, compared with adults in G1, those in G3 had 16% (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.77-0.90) reduced risk of all-cause mortality, and 23% (HR, 0.77; 95% CI, 0.67-0.89) reduced risk of CVD-specific mortality. The PAF of high (G3) vs. intermediate or low consumption of MedHi foods (G1+G2) with all-cause and CVD-specific mortality was 3.4% and 4.3%, respectively.; CONCLUSIONS: Consumption of foods with higher microbial concentrations is associated with a reduced risk of all-cause and CVD-specific mortality in US adults. © 2024. Springer-Verlag GmbH Germany, part of Springer Nature.

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  • 5.Transcription factor AP-2 gamma/Kruppel-like factor 10 axis is involved in miR-3656-related dysfunction of endothelial cells in hypertension

    • 关键词:
    • endothelial cell; hypertension; Kruppel-like factor 10; miR-3656;transcription factor AP-2 gamma;EXPRESSION; PROGRESSION
    • Ren, Yaxuan;Shi, Jikang;Liu, Sainan;Zhu, Wenfei;Shao, Aiyu;Qiao, Yichun;Li, Yong;Liu, Yunkai;Cheng, Yi;Liu, Yawen
    • 《JOURNAL OF HYPERTENSION》
    • 2023年
    • 41卷
    • 4期
    • 期刊

    Background: Dysfunction of endothelial cells links to microvascular rarefaction, reflecting the pathogenesis of hypertension. Our previous studies found that miR-3656 reduces nitric oxide generation and von Willebrand factor (vWF) cleavage, thereby retarding blood flow and potentially increasing blood pressure. In this paper, we investigated mechanism of transcription regulation contributing to miR3656-damaged endothelial cells in hypertension.Methods: The effects of miR-3656 on function of endothelial cells were analyzed on the basis of proliferation, migration, tube formation, and apoptosis. The mRNA level and protein level of genes were examined using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Dual-luciferase reporter assay was performed to confirm the binding between miR-3656 and 3 ' untranslated region (UTR) of transcription factor AP-2 gamma (TFAP2C). The binding between TFAP2C and the promoter region of Krppel-like factor 10 (KLF10) was confirmed by chromatin immunoprecipitation-qPCR assay.Results: miR-3656 impaired the cell proliferation, migration, tube formation, and apoptosis of endothelial cells. miR-3656 inhibited the expression of TFAP2C by directly targeting 3 ' UTR of TFAP2C; moreover, miR-3656induced injury of endothelial cells was rescued by TFAP2C overexpression. Furthermore, downregulated TFAP2C decreased KLF10 expression by binding to KLF10 promoter region, and upregulated KLF10 reversed the effects of silencing TFAP2C on endothelial cells. These inhibitory processes led to interference of miR-3656 to KLF10promoted function of endothelial cells. Conclusion: TFAP2C/KLF10 axis is involved in miR-3656related dysfunction of endothelial cells in hypertension. The 3 ' UTR of TFAP2C and KLF10 promoter region are the hubs of the TFAP2C/KLF10 axis.

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  • 7.Epidemiological status quo of hypertension in elderly population in Changchun, China: a cross-sectional study

    • 关键词:
    • hypertension; epidemiology; public health;RISK-FACTORS; PREVALENCE; AWARENESS; BURDEN; ADULTS; NATIONWIDE
    • Ren, Yaxuan;Shi, Jikang;Qiao, Yichun;Gu, Yulu;Li, Yong;Liu, Yunkai;Cheng, Yi;Liu, Yawen
    • 《BMJ OPEN》
    • 2022年
    • 12卷
    • 3期
    • 期刊

    Objectives To investigate the epidemiological status quo of hypertension in elderly population in Changchun, China, and provide a reference for the prevention and control strategies of hypertension of elderly population in this region. Design A cross-sectional study, as a part of a comprehensive project in Northeast China, was designed to perform in 10 districts in Changchun. Participants and setting A total of 6846 participants who were >= 60 years old were selected using a random sampling method. Main outcome measures The epidemiological status quo of hypertension. Results The prevalence of hypertension in Changchun was 52.6%. Among participants with hypertension enrolled in this study, 87.6% of the participants had been diagnosed with hypertension before the study, 69.1% was taking antihypertensive medications and 66.9% had effective blood pressure control. Obesity, widower/widow, history of diseases and family history of hypertension were risk factors of hypertension (all p<0.05). Participants with obesity, a personal history of heart coronary disease, or a family history of hypertension were susceptible to realising risks of hypertension (all p<0.05). However, participants with diabetes, hyperlipidaemia, or a family history of hypertension were difficult to control blood pressure within the normal range (all p<0.05). In addition, 92.6% participants taking antihypertensive medications used a single medication, and calcium channel blockers was the most commonly used antihypertensive medications in monotherapy. Conclusion The rates of awareness, treatment and control of hypertension are greater in Changchun than those in China, indicating that the prevention and control of hypertension in Changchun are effective. However, the prevalence of hypertension in the elderly population in China is lower than that in Changchun, also rendering Changchun a substantial challenge for the supervision of hypertension.

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  • 8.Incidence and Risk Factors of Progression from Prehypertension or Hypertension to Diabetes among Older Adults of Northeastern China: A Prospective Cohort Study

    • 关键词:
    • HYPERTENSION;INVOLVEMENT;DIABETES
    • LIANG Zhuo Shuai;SHI Ji Kang;TIAN Yu Yang;HU Xin Meng;REN Ya Xuan;LIU Sai Nan;WANG Yu Jian;CHENG Yi;LIU Ya Wen
    • 《生物医学与环境科学:英文版》
    • 2022年
    • 12期
    • 期刊

    Approximately two-thirds of patients with type 2 diabetes have hypertension. Moreover, blood pressure(BP) increases with hyperglycemia progression. The nexus between prehypertension or hypertension and diabetes entail

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  • 9.Circulating miR-3656 induces human umbilical vein endothelial cell injury by targeting eNOS and ADAMTS13: a novel biomarker for hypertension

    • 关键词:
    • ADAMTS13; endothelial cell; eNOS; hypertension; miR-3656;NITRIC-OXIDE SYNTHASE; THROMBOTIC MICROANGIOPATHY; INFLAMMATORYCYTOKINES; BLOOD-PRESSURE; MICRORNAS; EXPRESSION; RELEASE;ATHEROSCLEROSIS; GENE
    • Shi, Jikang;Ren, Yaxuan;Liu, Sainan;Zhao, Qian;Kong, Fei;Guo, Yanbo;Xu, Jiayi;Liu, Siyu;Qiao, Yichun;Li, Yong;Liu, Yunkai;Liu, Yawen;Cheng, Yi
    • 《JOURNAL OF HYPERTENSION》
    • 2022年
    • 40卷
    • 2期
    • 期刊

    Background: Hypertension, as one of the most common chronic diseases, is a major public health issue. Previous studies have shown that there are miRNAs differentially expressed in hypertensive patients. In addition, hypertension is closely related to endothelial dysfunction, and miRNAs have been identified as important molecular mediators for endothelial function. Therefore, it is necessary to identify specific miRNAs related to hypertension and explore their molecular mechanism in the progression of hypertension. Methods: We investigated the association of circulating levels of miR-3656 with hypertension. Furthermore, in-vitro studies were performed to investigate its possible mechanisms for hypertension in that the direct target genes of miR-3656 were confirmed using dual-luciferase reporter assay; moreover, the effects of miR-3656 on proliferation, migration, apoptosis, and microvascular rarefaction of HUVECs were investigated using MTS kit, wound-healing assay, FITC Annexin V apoptosis detection kit, and tube formation assay, correspondingly. Results: Circulating miR-3656 was upregulated in patients with hypertension. MiR-3656 suppressed the proliferation, migration, and angiogenesis of HUVECs, but promoted the apoptosis of HUVECs. In addition, eNOS and ADAMTS13 were direct target genes of miR-3656, and overexpression of eNOS and ADAMTS13 abolished the effect of miR-3656 on HUVECs. Conclusion: MiR-3656 is a potential biomarker for hypertension. MiR-3656 is involved in endothelial cellular injury implicated in hypertension by targeting eNOS and ADAMTS13.

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  • 10.C1QA, C1QB, and GZMB are novel prognostic biomarkers of skin cutaneous melanoma relating tumor microenvironment

    • 关键词:
    • GRANZYME-B; GRANULES
    • Liang, Zhuoshuai;Pan, Lingfeng;Shi, Jikang;Zhang, Lianbo
    • 《SCIENTIFIC REPORTS》
    • 2022年
    • 12卷
    • 1期
    • 期刊

    Skin cutaneous melanoma (SKCM) is the most lethal form of skin cancers owing to high invasiveness and high metastatic potential. Tumor microenvironment (TME) provides powerful evidences for discerning SKCM, raising the prospect to identify biomarkers of SKCM. Based on the transcriptome profiles of patients with SKCM and the corresponding clinical information from The Cancer Genome Atlas (TCGA), we used ESTIMATE algorithm to calculate ImmuneScore and StromalScore and identified the TME-Related differentially expressed genes (DEGs), than the intersected TME-Related DEGs were used for subsequent functional enrichment analysis. Protein-protein interaction (PPI) analysis was used to identify the functionality-related DEGs and univariate Cox regression analysis was used to identify the survival-related DEGs. Furthermore, SKCM-related DEGs were identified based on two Gene Expression Omnibus (GEO) datasets. Finally, we intersected functionality-related DEGs, survival-related DEGs, and SKCM-related DEGs, ascertaining that six DEGs (CCL4, CXCL10, CCL5, GZMB, C1QA, and C1QB) function as core TME-related genes (CTRGs). Significant differences of GZMB, C1QA, and C1QB expressions were found in gender and clinicopathologic staging of SKCM. High levels of GZMB, C1QA, and C1QB expressions were associated with favorable prognosis. Gene set enrichment analysis (GSEA) showed that cell-cell interaction, cell behavior, and intracellular signaling transduction may be mainly involved in both C1QA, C1QB and GZMB expressions and metabolism of phospholipid and amino acid, transcription, and translation may be implicated in low GZMB expressions. C1QA, C1QB, and GZMB are novel SKCM-relating CTRGs, providing promising immune-related prognostic biomarkers for SKCM.

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