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Elevated peripheral levels of receptor-interacting protein kinase 1(RIPK1)and IL-8 as biomarkers of human amyotrophic lateral sclerosis

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Signal Transduction and Targeted Therapy 2024年第1期9卷 271-278页

作者： Jun Wei Min Li Zhi Ye Xinqian Hu Xiaoyan He Jia Wang Gaofeng Chen Chengyu Zou Daichao Xu Hongbing Zhang Junying Yuan Yunhong Zha Institute of Neural Regeneration and Repair and Department of Neurology The First College of Clinical Medical ScienceYichang Central HospitalCollege of Basic Medical ScienceChina Three Gorges UniversityHubei Province Clinical Medical Research Center for Rare Diseases of Nervous SystemYichang 443000China Interdisciplinary research center on biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai Key Laboratory of Aging StudiesShanghai 201210China State Key Laboratory of Common Mechanism research for Major Diseases Haihe Laboratory of Cell EcosystemDepartment of PhysiologyInstitute of Basic Medical Sciences and School of Basic MedicineChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Amyotrophic lateral sclerosis(ALS)is a devastating fatal neurodegenerative disease with no cure.Receptor-interacting protein kinase 1(RIPK1)has been proposed to mediate pathogenesis of ALS.Primidone has been identified as an old drug that can also inhibit RIPK1 kinase.We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1G93A mice and ALS patients.SOD1G93A mice treated with primidone showed significant delay of symptomatic onset and improved motor performance.One-hundred-sixty-two ALS participants dosed daily with primidone(62.5 mg)completed 24-week follow-up.A significant reduction was showed in serum levels of RIPK1 and IL-8,which were significantly higher in ALS patients than that of healthy controls(P<0.0001).Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms(P<0.05).Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients.Repurposing primidone may provide a promising therapeutic strategy for ALS.The effect of primidone for the treatment of other inflammatory diseases may also be considered,since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome(CRS).(ChiCTR2200060149).

关键词： RIPK1 diseases Serum

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Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner

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Protein & Cell 2024年第1期15卷 36-51页

作者： Jinghui Lei Xiaoyu Jiang Daoyuan Huang Ying Jing Shanshan Yang Lingling Geng Yupeng Yan Fangshuo Zheng Fang Cheng Weiqi Zhang Juan Carlos Izpisua Belmonte Guang-Hui Liu Si Wang Jing Qu Advanced Innovation center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China aging Translational Medicine center Intermational Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China National Laboratory of Biomacromolecules CAs Center for Excellence in BiomacromoleculesInstitute of BiophysicsBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National center for Bioinformation Beijing 100101China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish center for Education and research Beijing 101408China aging Biomarker Consortium China Altos Labs San DiegoCA 92121United State

Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological conditions.However,its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive.Here,we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-ia-deficient human vascular cells including vascular endothelial cells,vascular smooth muscle cells,and mesenchymal stem cells(MsCs),as a platform for discovering cell type-specific hypox-ia-induced response mechanisms.Through comparative molecular profiling across cell types under normoxic and hypoxic conditions,we provide insight into the indispensable role of HIF-1αin the promotion of ischemic vascular regeneration.We found human MSCs to be the vascular cell type most susceptible to HIF-1a deficiency,and that transcriptional inactivation of ANKZF1,an effector of HIF-1a,impaired pro-angiogenic processes.Altogether,our findings deepen the understanding of HIF-ia in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

关键词： HIF-1 human ESC vascular cell regeneration

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Nanotechnology’s frontier in combatting infectious and inflammatory diseases:prevention and treatment

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Signal Transduction and Targeted Therapy 2024年第3期9卷 998-1047页

作者： Yujing Huang Xiaohan Guo Yi Wu Xingyu Chen Lixiang Feng Na Xie Guobo Shen Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China Hospitaland West China School of Basic Medical Sciences and Forensic MedicineSichuan Universityand Collaborative Innovation Center for BiotherapyChengdu 610041China

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases,which continuously pose one of the most serious threats to human health,attributed to factors such as the emergence of new pathogens,increasing drug resistance,changes in living environments and lifestyles,and the aging population.Despite rapid advancements in mechanistic research and drug development for these diseases,current treatments often have limited efficacy and notable side effects,necessitating the development of more effective and targeted anti-inflammatory therapies.In recent years,the rapid development of nanotechnology has provided crucial technological support for the prevention,treatment,and detection of inflammation-associated diseases.Various types of nanoparticles(NPs)play significant roles,serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability.NPs can also directly combat pathogens and inflammation.In addition,nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases.This review categorizes and characterizes different types of NPs,summarizes their applications in the prevention,treatment,and detection of infectious and inflammatory diseases.It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects.In conclusion,nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.

关键词： prevention inflammatory treatment

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Insights and implications of sexual dimorphism in osteoporosis

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Bone research 2024年第1期12卷 20-49页

作者： Yuan-Yuan Zhang Na Xie Xiao-Dong Sun Edouard C.Nice Yih-Cherng Liou Canhua Huang Huili Zhu Zhisen Shen Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China West China School of basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China Department of Biochemistry and Molecular biology Monash UniversityClaytonVIC 3800Australia Department of Biological Sciences Faculty of ScienceNational University of SingaporeSingapore 117543Republic of Singapore Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China Hospitaland West China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityChengdu 610041China Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education Department of Reproductive MedicineWest China Second University Hospital of Sichuan UniversityChengduChina Department of Otorhinolaryngology and Head and Neck Surgery The Affiliated Lihuili HospitalNingbo University315040 NingboZhejiangChina

Osteoporosis,a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture,has led to a high risk of fatal osteoporotic fractures worldwide.Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis,with sex-specific differences in epidemiology and pathogenesis.Specifically,females are more susceptible than males to osteoporosis,while males are more prone to disability or death from the disease.To date,sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells.Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men.This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis,mainly in a population of aging patients,chronic glucocorticoid administration,and diabetes.Moreover,we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men.Additionally,the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.

关键词： osteoporosis epidemiology overcome

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Vacuolar protein sorting protein 41(VPS41) at an intersection of endosomal traffic in neurodegenerative disease

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Neural Regeneration research 2019年第7期14卷 1210-1212页

作者： Edward F.Griffin Kim A.Caldwell Guy A.Caldwell Department of Biological Sciences The University of Alabama Departments of Neurology and Neurobiology University of Alabama at Birmingham School of Medicine center for Neurodegeneration and Experimental Therapeutics University of Alabama at Birmingham School of Medicine nathan shock center of excellence for basic research in the biology of aging University of Alabama at Birmingham

Alzheimer’s and Parkinson’s diseases are neurodegenerative disorders pathologically classified by the accumulation of amyloidogenic proteins into insoluble inclusions within the brain.Specifically,amyloid plaques in the brains of Alzheimer’s disease patients are comprised of amyloid-β(Aβ)peptide,the product of sequential cleavage of the amyloid precursor protein byβ-andγ-secretases.Similarly,α-synuclein is a major component of Lewy bodies associated with Parkinson’s disease.

关键词： commissural axon guidance pathologically

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Hypermethylation in H3K9me3 regions characterizes the centenarian methylomes in healthy aging

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National Science Review 2023年第6期10卷 60-63页

作者： Fu-Hui Xiao Hao-Tian Wang Xiao-Qiong Chen Ming-Xia Ge Dongjing Yan Xing-Li Yang Li-Qin Yang Rong Lin Rong-Hui Guo Wen Zhang Nelson Leung-Sang Tang Yonghan He Jumin Zhou Wang-Wei Cai Qing-Peng Kong State Key Laboratory of Genetic Resources and Evolution Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Key Laboratory of Healthy Aging Study Kunming Institute of ZoologyChinese Academy of Sciences KIZ/CUHK Joint Laboratory of Bioresources and Molecular research in Common Diseases Kunming College of Life Science University of Chinese Academy of Sciences Department of Biochemistry and Molecular biology Hainan Medical College Department of biology Hainan Medical College Department of Chemical Pathology and Laboratory for Genetics of Disease Susceptibility Li Ka Shing Institute of Health Sciences and School of Biomedical Sciences Faculty of Medicine The Chinese University of Hong Kong Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology CAS center for excellence in Animal Evolution and Genetics Chinese Academy of Sciences

Centenarians,as excellent examples of extreme yet successful aging,not only display a much longer lifespan but can also delay or even escape major agerelated diseases,such as cardiovascular disorders,neurodegenerative diseases,and cancer [1].Studies have suggested that genetic factors account for 20%-30%of human longevity [2];however,only a handful of longevity-associated genes/mutations have been observed in long-lived individuals,even with the use of genome-wide scanning/sequencing assays [3,4].In contrast,evidence has shown the crucial roles of epigenetic alternations in aging and age-related diseases [5],suggesting that epigenetic modifications play central roles in human healthy aging.Thus,a comprehensive analysis of the epigenomic landscape of centenarians is urgently needed.

关键词： LONGEVITY DNA

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A novel peptide-based probe^(99m)Tc-PEG_(6)-RD-PDP2 for the molecular imaging of tumor PD-L2 expression

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Chinese Chemical Letters 2022年第7期33卷 3497-3501页

作者： Qi Luo Yunwei Zhang Zihua Wang Yining Sun Linqing Shi Yue Yu Jiyun Shi Zhiyuan Hu Fan Wang Guangzhou Laboratory Guangzhou 510005China Medical Isotopes research center and Department of Radiation Medicine State Key Laboratory of Natural and Biomimetic DrugsSchool of Basic Medical SciencesPeking UniversityBeijing 100191China Fujian Provincial Key Laboratory of Brain aging and Neurodegenerative Diseases School of Basic Medical SciencesFujian Medical UniversityFuzhou 350122China Key Laboratory of Protein and Peptide Pharmaceuticals CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Standardization and Measurement for Nanotechnology CAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology of ChinaBeijing 100190China

Tumor-related PD-L2 expression is associated with the clinical efficacy of PD-1/PD-L1 blockade therapy.PD-L2-specific imaging can help selecting patients for appropriate immunotherapy.In this study,a PD-L2-targeting peptide(PDP2)was screened by the one-bead one-compound combinatorial library approach.Using the retro-inverso D-peptide of PDP2(RD-PDP2)and PEGylation strategies,we developed a novel Tc-99m-labeled PD-L2-targeting peptide as a SPECT tracer(^(99m)Tc-PEG_(6)-RD-PDP2)for imaging of tumor PD-L2 expression.The radiolabeling yield of ^(99m)Tc-PEG_(6)-RD-PDP2 was greater than 95%by the standard HYNIC/tricine/TPPTS labeling procedure.^(99m)Tc-PEG_(6)-RD-PDP2 displayed high PD-L2-binding specificity both in vitro and in vivo.SPECT/CT imaging with^(99m)Tc-PEG_(6)-RD-PDP2 showed that the A549-PD-L2tumors were clearly visualized,whereas the signals in PD-L2-negative A549 tumors were much lower.In vivo blocking study suggested that the tumor uptake of^(99m)Tc-PEG_(6)-RD-PDP2 was PD-L2 specifically mediated.^(99m)Tc-PEG_(6)-RD-PDP2 is a promising SPECT probe for the non-invasive imaging of tumor PD-L2expression and has a great potential in guiding the anti-PD-1 or anti-PD-L1 immunotherapy of cancer.

关键词： PD-L2 Peptide probe SPECT imaging Immunotherapy

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The landscape of aging

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Science China(Life Sciences) 2022年第12期65卷 2354-2454页

作者： Yusheng Cai Wei Song Jiaming Li Ying Jing Chuqian Liang Liyuan Zhang Xia Zhang Wenhui Zhang Beibei Liu Yongpan An Jingyi Li Baixue Tang Siyu Pei Xueying Wu Yuxuan Liu Cheng-Le Zhuang Yilin Ying Xuefeng Dou Yu Chen Fu-Hui Xiao Dingfeng Li Ruici Yang Ya Zhao Yang Wang Lihui Wang Yujing Li Shuai Ma Si Wang Xiaoyuan Song Jie Ren Liang Zhang Jun Wang Weiqi Zhang Zhengwei Xie Jing Qu Jianwei Wang Yichuan Xiao Ye Tian Gelin Wang Ping Hu Jing Ye Yu Sun Zhiyong Mao Qing-Peng Kong Qiang Liu Weiguo Zou Xiao-Li Tian Zhi-Xiong Xiao Yong Liu Jun-Ping Liu Moshi Song Jing-Dong J.Han Guang-Hui Liu State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Frontier Science center for Immunology and Metabolism Medical Research InstituteCollege of Life SciencesWuhan UniversityWuhan 430071China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Stem Cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and HealthChinese Academy of SciencesShanghai 200031China CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China Peking University International Cancer Institute Peking University Health Science CenterPeking UniversityBeijing 100191China School of Pharmaceutical Sciences Tsinghua UniversityBeijing 100084China State Key Laboratory of Molecular Developmental biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China School of Pharmaceutical Sciences Beijing Advanced Innovation Center for Structural BiologyMinistry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyTsinghua UniversityBeijing 100084China Colorectal Cancer center/Department of Gastrointestinal Surgery Shanghai Tenth People’s Hospital Affiliated to Tongji UniversityShanghai 200072China Department of Geriatrics Medical Center on Aging of Shanghai Ruijin HospitalShanghai Jiaotong University School of MedicineShanghai 200025China International Laboratory in Hematology and Cancer Shanghai Jiaotong University School of Med

aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.

关键词： aging mechanism intervention

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4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

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Protein & Cell 2023年第3期14卷 202-216页

作者： Yifang He Qianzhao Ji Zeming Wu Yusheng Cai Jian Yin Yiyuan Zhang Sheng Zhang Xiaoqian Liu Weiqi zhang Guang-Hui Liu Si Wang Moshi Song Jing Qu State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem Cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijing 10o101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China University of Chinese Academy of Sciences Beijing 100049China Advanced Innovation center for Human Brain Protection and National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing100053China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National center for Bioinformation Beijing 100101China National Laboratory of Biomacromolecules CAs Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101 China State Key Laboratory of Brain and Cognitive Science CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of Brain-Intelligence Technology(Shanghai)Institute of BiophysicsChinese Academy of SciencesBeijing 100101China aging Translational Medicine center Intermational Center for Aging and CancerBejing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China The Fifth People's Hospital of Chongqing Chongqing 400062China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem celis(hMSCs).Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration,increases mitochondrial reactive oxygen species(Ros)production,and accelerates cellular senescence.Mechanistically,the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes,especially several key subunits of complex III including UQCRC2.Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs.These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis,particularly for the mitochondrial respiration complex Il,thus providing a new potential target to counteract human stem cell senescence.

关键词： 4E-BP1 mitochondria aging

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APOE-mediated suppression of the lncRNA MEG3 protects human cardiovascular cells from chronic inflammation

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Protein & Cell 2023年第12期14卷 908-913页

作者： Hongkai Zhao Kuan Yang Yiyuan Zhang Hongyu Li Qianzhao ji Zeming Wu Shuai Ma Si Wang Moshi Song Guang-Hui Liu Qiang Liu Weiqi Zhang Jing Qu Division of Life Sciences and Medicine School of Life SciencesUniversity of Science and Technology of ChinaHefei 230001China State Key Laboratory of Stem Cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Universityof Chinese Academy of Sciences Beijing100049China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Advanced Innovation center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical University.Beijing100053China aging Translational Medicine center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China aging Biomarker Consortium Beijing 100101China 12Division of Life Sciences and Medicine Institute on Aging and Brain DisordersThe First Affiliated Hospital of USTCHefei National Laboratory for Physical Sciences at the MicroscaleUniversity of Science and Technology of ChinaHefei 230026China Neurodegenerative Disease research center University of Science and Technology of ChinaHefei 230026China CAS Key Laboratory of Brain Function and Disease University of Science and Technology of ChinaHefei 230026China center for excellence in Animal Evolution and Genetics Chinese Academy of SciencesKunming 650201China

Dear Editor,Cardiovascular diseases(CVDs)are the leading cause of death world-wide.Thus,diagnosing and treating CVD remains at the forefront for clinicians while identifying targetable disease mechanisms in preclinical models are focus areas for researchers and drug developers(Cai et al.,2022a).The polymorphic protein apolipoprotein E(APOE),central to lipid transport and metabolism,is well-recognized for the role of its isoforms as important predictors for human cardiovascular disorders and neurodegenerative diseases(Tudorache et al.,2017).Plasma APOE is generated primarily from liver hepatocytes,accounting for around 75%of the APOE production from the whole body(Getz and Reardon,2009),and plays important functional roles in monocytes/macrophages,adipocytes,and the central nervous system(Kockx et al.,2018).However,despite the fact that APOE is widely expressed in different mammalian cells,studies on the functional roles of APOE mostly focus on its extracellular secreted form,and the specific effects of APOE,particularly intracellular form in cell types closely related to human cardiovascular diseases are therefore still poorly understood.

关键词： cardiovascular metabolism

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