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atherosclerosis,its risk factors,and cognitive impairment in older adults

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Journal of Geriatric Cardiology 2020年第7期17卷 434-440页

作者： Yun-Li XING Michael A Chen Ying SUN Moni B Neradilek Xi-Ting WU Dai ZHANG Wei HUANG Yining CUI Qi-Qi YANG Hong-Wei LI Xue-Qiao ZHAO Department of Geriatrics and Gerontology Beijing Friendship HospitalCapital Medical UniversityBeijingChina Division of Cardiology University of WashingtonSeattleWAUSA The Mountain-Whisper-Light Statistics SeattleWAUSA Cardiovascular Center Beijing Friendship HospitalCapital Medical UniversityBeijingChina

Objective To examine the association of atherosclerotic cardiovascular disease(ASCVD)and its risk factors with cognitive impairment in older adults.Methods Six hundred and fourteen subjects,aged≥65 years,from one center(2016–2018)underwent clinical,laboratory assessments and the Montreal Cognitive Assessment(Mo CA).Using regression analysis,the relationship between ASCVD and its risk factors was evaluated in subjects with and without cognitive impairment(MoCA score<26).Results Older age(b=-1.3 per 5 years,95%CI:-1.7 to-0.9,P<0.001),history of stroke(b=-1.6,95%CI:-3.0 to-0.3,P=0.01),and myocardial infarction(MI;b=-2.2,95%CI:-3.6 to-0.8,P=0.003)were independently associated with lower MoCA scores,whereas more education(b=1.5 per 3 years,95%CI:1.1 to 1.9,P<0.001),higher body mass index(BMI;b=0.5 per 3 kg/m^2,95%CI:0.0 to 1.0,P=0.04),higher estimated glomerular filtration rate(eGFR;b=0.8 per 15 U,95%CI:0.1 to 1.4,P=0.03),left ventricular ejection fraction(LVEF;b=0.4 per 5%,95%CI:0 to 0.8,P=0.04)and statin use(b=1.3,95%CI:0.3 to 2.3,P=0.01)were associated with a higher MoCA score.Cognitive impairment was independently associated with older age(OR=1.51 per 5 yrs,95%CI:1.28 to 1.79,P<0.001),less education(OR=0.55 per 3 years,95%CI:0.45 to 0.68,P<0.001),lower BMI(OR=0.78 per 3 kg/m^2,95%CI:0.62 to 0.98,P=0.03)and higher levels of high sensitivity c-reactive protein(hsCRP;OR=1.08 per 1 mg/L,95%CI:1.02 to 1.15,P=0.01).Conclusions Beyond age,cognitive impairment was associated with prior MI/stroke,higher hsCRP,statin use,less education,lower eGFR,BMI and LVEF.

关键词： atherosclerosis Cognitive impairment Correlation Older adults Risk factors

Recent advances of mechanosensitive genes in vascular endothelial cells for the formation and treatment of atherosclerosis

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Genes & Diseases 2024年第3期11卷 206-219页

作者： Shuyu Li Zichen Xu Yi Wang Lizhao Chen Xiangxiu Wang Yanghao Zhou Daoxi Lei Guangchao Zang Guixue Wang Key Laboratory of Biorheological Science and Technology of Ministry of Education National and Local Joint Engineering Laboratory for Vascular ImplantsBioengineering College of Chongqing UniversityChongqing 400030China College of Basic Medical Sciences Chongqing Medical UniversityChongqing 400016China Department of Neurosurgery Daping HospitalArmy Medical Center of PLAArmy Medical UniversityChongqing 400042China

Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide.Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells,and it plays an important role in gene regulation of pro-inflammatory,pro-thrombotic,pro-oxidative stress,and cell permeability.Many impor-tant endothelial cell mechanosensitive genes have been discovered,including KLK10,CCN gene family,NRP2,YAP,TAZ,HIF-1α,NF-kB,FOS,JUN,TFEB,KLF2/KLF4,NRF2,and ID1.Some of them have been intensively studied,whereas the relevant regulatory mechanism of other genes remains unclear.Focusing on these mechanosensitive genes will provide new strategies for therapeutic intervention in atherosclerotic vascular disease.Thus,this article reviews the mechanosensitive genes affecting vascular endothelial cells,including classical pathways and some newly screened genes,and summarizes the latest research progress on their roles in the pathogenesis of atherosclerosis to reveal effective therapeutic targets of drugs and provide new insights foranti-atherosclerosis.

关键词： atherosclerosis Blood flow Endothelial cell Mechanosensitive gene Therapeutic target

Research Advance of Chinese Medicine in Treating atherosclerosis:Focus on Lipoprotein-Associated Phospholipase A2

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Chinese Journal of Integrative Medicine 2024年第3期30卷 277-288页

作者： WANG Lu-ming ZHANG Wen-lan LYU Nuan SUO Yan-rong YANG Lin YU Bin JIANG Xi-juan School of Integrative Medicine Tianjin University of Traditional Chinese MedicineTianjin301617China Department of Traditional Chinese Medicine Ganzhou People’s HospitalGanzhouJiangxi Province341000China School of Medical Technology Tianjin University of Traditional Chinese MedicineTianjin301617China

As a serious cardiovascular disease,atherosclerosis(AS)causes chronic inflammation and oxidative stress in the body and poses a threat to human health.Lipoprotein-associated phospholipase A2(Lp-PLA2)is a member of the phospholipase A2(PLA2)family,and its elevated levels have been shown to contribute to AS.Lp-PLA2 is closely related to a variety of lipoproteins,and its role in promoting inflammatory responses and oxidative stress in AS is mainly achieved by hydrolyzing oxidized phosphatidylcholine(ox PC)to produce lysophosphatidylcholine(lyso PC).Moreover,macrophage apoptosis within plaque is promoted by localized Lp-PLA2 which also promotes plaque instability.This paper reviews those researches of Chinese medicine in treating AS via reducing Lp-PLA2 levels to guide future experimental studies and clinical applications related to AS.

关键词： lipoprotein-associated phospholipase A2 atherosclerosis inflammation oxidative stress apoptosis Chinese medicine

Endothelial METRNL determines circulating METRNL level and maintains endothelial function against atherosclerosis

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1568-1587页

作者： Sili Zheng Zhiyong Li Jie Song Pin Wang Jian Xu Wenjun Hu Yi Shi Qi Qi Zhuwei Miao Yunfeng Guan Chaoyu Miao Department of Pharmacology Second Military Medical University/Naval Medical UniversityShanghai 200433China Changhai Hospital Second Military Medical University/Naval Medical UniversityShanghai 200433China Zhongshan Hospital Fudan UniversityShanghai 200032China

METRNL is a recently identified secreted protein with emerging functions.This study is to find major cellular source of circulating METRNL and to determine METRNL novel function.Here,we show METRNL is abundant in human and mouse vascular endothelium and released by endothelial cells using endoplasmic reticulum-Golgi apparatus pathway.By creating endothelial cell-specific Metrnl knockout mice,combined with bone marrow transplantation to produce bone marrow-specific deletion of Metrnl,we demonstrate that most of circulating METRNL(approximately 75%)originates from the endothelial cells.Both endothelial and circulating METRNL decrease in atherosclerosis mice and patients.By generating endothelial cell-specific Metrnl knockout in apolipoprotein E-deficient mice,combined with bone marrow-specific deletion of Metrnl in apolipoprotein E-deficient mice,we further demonstrate that endothelial METRNL deficiency accelerates atherosclerosis.Mechanically,endothelial METRNL deficiency causes vascular endothelial dysfunction including vasodilation impairment via reducing eNOS phosphorylation at Ser1177 and inflammation activation via enhancing NFκB pathway,which promotes the susceptibility of atherosclerosis.Exogenous METRNL rescues METRNL deficiency induced endothelial dysfunction.These findings reveal that METRNL is a new endothelial substance not only determining the circulating METRNL level but also regulating endothelial function for vascular health and disease.METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis.

关键词： METRNL Secreted protein Endothelium Endothelial function Bone marrow atherosclerosis

LOX-1 Regulation in Anti-atherosclerosis of Active Compounds of Herbal Medicine:Current Knowledge and the New Insight

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Chinese Journal of Integrative Medicine 2023年第2期29卷 179-185页

作者： YAO Si-jie LAN Tao-hua ZHANG Xin-yu ZENG Qiao-huang XU Wen-jing LI Xiao-qing HUANG Gui-bao LIU Tong LYU Wei-hui JIANG Wei State Key Laboratory of Dampness Syndrome of Chinese Medicine Department of Cardiologythe Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510020China Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases Guangzhou 510020China The Second Clinical Medical College of Guangzhou University of Chinese Medicine Guangzhou 510405China

Lectin-like oxidized low-density lipoprotein receptor-1(LOX-1)have recently been identified to be closely related to the occurrence and development of atherosclerosis(AS).A growing body of evidence has suggested Chinese medicine takes unique advantages in preventing and treating As.In this review,the related research progress of AS and LOX-1 has been summarized.And the anti-As effects of 10 active components of herbal medicine through LOX-1 regulation have been further reviewed.As a potential biomarker and target for intervention in AS,LOX-1 targeted therapy might provide a promising and novel approach to atherosclerotic prevention andtreatment.

关键词： atherosclerosis herbal medicine lectin-like oxidized low-density lipoprotein receptor-1 targeted therapy

Long-term, in vivo therapeutic effects of a single dose of miR-145 micelles for atherosclerosis

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Bioactive Materials 2023年第9期27卷 327-336页

作者： Deborah D.Chin Neil Patel Woori Lee Sonali Kanaya Jackson Cook Eun Ji Chung Department of Biomedical Engineering University of Southern CaliforniaLos AngelesCA90089United States Division of Vascular Surgery and Endovascular Therapy Department of SurgeryKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90033United States Mork Family Department of Chemical Engineering and Materials Science University of Southern CaliforniaLos AngelesCA90089United States Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90033United States Division of Nephrology and Hypertension Department of MedicineKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90033United States Norris Comprehensive Cancer Center Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90089United States

atherosclerosis is a chronic inflammatory disease that is characterized by the build-up of lipid-rich plaques in the arterial walls. The standard treatment for patients with atherosclerosis is statin therapy aimed to lower serum lipid levels. Despite its widespread use, many patients taking statins continue to experience acute events. Thus, to develop improved and alternative therapies, we previously reported on microRNA-145 (miR-145 micelles) and its ability to inhibit atherosclerosis by targeting vascular smooth muscle cells (VSMCs). Importantly, one dose of miR-145 micelles significantly abrogated disease progression when evaluated two weeks post-administration. Thus, in this study, to evaluate how long the sustained effects of miR-145 micelles can be maintained and towards identifying a dosing regimen that is practical for patients with chronic disease, the therapeutic effects of a single dose of miR-145 micelles were evaluated for up to two months in vivo. After one and two months post-treatment, miR-145 micelles were found to reduce plaque size and overall lesion area compared to all other controls including statins without causing adverse effects. Furthermore, a single dose of miR-145 micelle treatment inhibited VSMC transdifferentiation into pathogenic macrophage-like and osteogenic cells in plaques. Together, our data shows the long-term efficacy and sustained effects of miR-145 micelles that is amenable using a dosing frequency relevant to chronic disease patients.

关键词： MicroRNA-145 atherosclerosis Vascular smooth muscle cell Nanoparticle Gene therapy

Quercetin Attenuates atherosclerosis via Modulating Apelin Signaling Pathway Based on Plasma Metabolomics

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Chinese Journal of Integrative Medicine 2023年第12期29卷 1121-1132页

作者： LIU Li-qun ZHANG Peng QI Ying-zi LI Hui JIANG Yue-hua YANG Chuan-hua The First Clinical Medical College Shandong University of Traditional Chinese MedicineJinan(250355)China College of Integrated Chinese and Western Medicine Binzhou Medical UniversityYantaiShandong Province(264000)China Health College Shandong University of Traditional Chinese MedicineJinan(250355)China Department of Pharmacy Ruijin HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai(200050)China Central Laboratory Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan(250014)China Department of Cardiovascular Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan(250014)China

Objective:To interpret the pharmacology of quercetin in treatment of atherosclerosis(AS).Methods:Fourteen apolipoprotein E-deficient(ApoE^(-/-))mice were divided into 2 groups by a random number table:an AS model(ApoE^(-/-))group and a quercetin treatment group(7 in each).Seven age-matched C57 mice were used as controls(n=7).Quercetin[20 mg/(kg·d)]was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation.Besides morphological observation,the distribution of CD11b,F4/80,sirtuin 1(Sirt1)and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence.Ultra-performance liquid chromatography/tandem mass spectrometry(UPLC-MSC/MS)was performed to study the pharmacology of quercetin against AS.Then,simultaneous administration of an apelin receptor antagonist(ML221)with quercetin was conducted to verify the possible targets of quercetin.Key proteins in apelin signaling pathway,such as angiotensin domain type 1 receptor-associated proteins(APJ),AMP-activated protein kinase(AMPK),peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α),tissue plasminogen activator(TPA),uncoupling protein 1(UCP1)and angiotensinⅡreceptor 1(AT1R),were assayed by Western blot.Results:Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE^(-/-)aortas in vivo.Quercetin decreased the densities of CD11b,F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE^(-/-)mice(all P<0.05).Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls.Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways.Quercetin treatment increased the protein expressions of APJ,AMPK,PGC-1α,TPA and UCP1,while decreased the AT1R level(all P<0.05).After the apelin pathway was blocked by ML221,the effect of quercetin was aba

关键词： quercetin atherosclerosis plasma metabonomics apelin signaling pathway

Top Five Stories of the Cellular Landscape and Therapies of atherosclerosis:Current Knowledge and Future Perspectives

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Current Medical Science 2024年第1期44卷 1-27页

作者： Qi PAN Cheng CHEN Yue-jin YANG State Key Laboratory of Cardiovascular Disease Department of CardiologyFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100037China

atherosclerosis(AS)is characterized by impairment and apoptosis of endothelial cells,continuous systemic and focal inflammation and dysfunction of vascular smooth muscle cells,which is documented as the traditional cellular paradigm.However,the mechanisms appear much more complicated than we thought since a bulk of studies on efferocytosis,transdifferentiation and novel cell death forms such as ferroptosis,pyroptosis,and extracellular trap were reported.Discovery of novel pathological cellular landscapes provides a large number of therapeutic targets.On the other side,the unsatisfactory therapeutic effects of current treatment with lipid-lowering drugs as the cornerstone also restricts the efforts to reduce global AS burden.Stem cell-or nanoparticle-based strategies spurred a lot of attention due to the attractive therapeutic effects and minimized adverse effects.Given the complexity of pathological changes of AS,attempts to develop an almighty medicine based on single mechanisms could be theoretically challenging.In this review,the top stories in the cellular landscapes during the initiation and progression of AS and the therapies were summarized in an integrated perspective to facilitate efforts to develop a multi-targets strategy and fill the gap between mechanism research and clinical translation.The future challenges and improvements were also discussed.

关键词： atherosclerosis transdifferentiation extracellular traps efferocytosis stem cell nanoparticles

Natural products:potential therapeutic agents for atherosclerosis

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Chinese Journal of Natural Medicines 2022年第11期20卷 830-845页

作者： CHENG Xiaobei ZHAO Caili JIN Zhiwei HU Jianping ZHANG Zhenzhen ZHANG Chao State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 210009China Institute of Veterinary Medicine Jiangsu Academy of Agricultural SciencesNanjing 210014China

atherosclerosis(AS)is an invisible killer among cardiovascular diseases(CVD),which has seriously threatened the life of quality.The complex pathogenesis of AS involves multiple interrelated events and cell types,such as macrophages,endothelial cells,vascular smooth muscle cells and immune cells.Currently,the efficacy of recommended statin treatment is not satisfactory.Natural products(NPs)have attracted increasing attention with regard to their broad structural diversity and biodiversity,which makes them a promising library in the demand for lead compounds with cardiovascular protective bio-activity.NPs can preclude the development of AS by regulating lipid metabolism,ameliorating inflammation,stabilizing plaques,and remodeling the gut microbiota,which lays a foundation for the application of NPs in clinical therapeutics.

关键词： atherosclerosis Cardiovascular diseases Pathogenesis Target Natural products