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high-density lipoprotein regulates angiogenesis by affecting autophagy via miRNA-181a-5p

Science China(Life Sciences) 2024年第2期67卷 286-300页

作者： Bi-Ang Kang Hua-Ming Li Ya-Ting Chen Meng-Jie Deng Yan Li Yue-Ming Peng Jian-Jun Gao Zhi-Wei Mo Jia-Guo Zhou Zhi-Jun Ou Jing-Song Ou Division of Cardiac Surgery Cardiovascular Diseases InstituteThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases Guangzhou 510080China NHC key Laboratory of Assisted Circulation(Sun Yat-sen University) Guangzhou 510080China Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases Guangzhou 510080China Division of Vascular Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Pharmacology Cardiac and Cerebral Vascular Research CenterZhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China Division of Hypertension and Vascular Diseases Department of CardiologyCardiovascular Diseases InstituteThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Guangdong Provincial Key Laboratory of Brain Function and Disease Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China

We previously demonstrated that normal high-density lipoprotein(nHDL)can promote angiogenesis,whereas HDL from patients with coronary artery disease(d HDL)is dysfunctional and impairs angiogenesis.Autophagy plays a critical role in angiogenesis,and HDL regulates autophagy.However,it is unclear whether n HDL and d HDL regulate angiogenesis by affecting autophagy.Endothelial cells(ECs)were treated with n HDL and d HDL with or without an autophagy inhibitor.Autophagy,endothelial nitric oxide synthase(e NOS)expression,miRNA expression,nitric oxide(NO)production,superoxide anion(O2^(·-))generation,EC migration,and tube formation were evaluated.n HDL suppressed the expression of miR-181a-5p,which promotes autophagy and the expression of e NOS,resulting in NO production and the inhibition of O2^(·-)generation,and ultimately increasing in EC migration and tube formation.d HDL showed opposite effects compared to n HDL and ultimately inhibited EC migration and tube formation.We found that autophagy-related protein 5(ATG5)was a direct target of miR-181a-5p.ATG5 silencing or miR-181a-5p mimic inhibited n HDL-induced autophagy,e NOS expression,NO production,EC migration,tube formation,and enhanced O2^(·-)generation,whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of d HDL.ATG5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null(LDLr^(-/-))mice when compared to C57BL/6 mice.ATG5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr^(-/-)mice.Taken together,nHDL was able to stimulate autophagy by suppressing miR-181a-5p,subsequently increasing e NOS expression,which generated NO and promoted angiogenesis.In contrast,d HDL inhibited angiogenesis,at least partially,by increasing miR-181a-5p expression,which decreased autophagy and e NOS expression,resulting in a decrease in NO production and an increase in O2^(·-)generation.Our findings reveal a novel mechanism by which HDL affects angiogenesis b

关键词： high-density lipoprotein angiogenesis autophagy ATG5 miRNA endothelial nitric oxide synthase

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Lenvatinib-and vadimezan-loaded synthetic high-density lipoprotein for combinational immunochemotherapy of metastatic triple-negative breast cancer

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3726-3738页

作者： Chao Zheng Wen Zhang Jinming Wang Yihui Zha Fengqin Xiong Ying Cai Xiang Gong Binyu Zhu Helen He Zhu Hao Wang Yaping Li Pengcheng Zhang China State Institute of Pharmaceutical Industry Shanghai 201203China State Key Laboratory of Drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Yantai Key Laboratory of Nanomedicine&Advanced Preparations Yantai Institute of Materia MedicaYantai 264000China State Key Laboratory of Oncogenes and Related Genes Renji-Med-X Stem Cell Research CenterDepartment of UrologyRen Ji HospitalSchool of Medicine and School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai 200135China University of Chinese Academy of Sciences Beijing 100049China Bohai Rim Advanced Research Institute for Drug Discovery Yantai 264000China

Metastatic triple-negative breast cancer(TNBC)is the most aggressive type of breast cancer.Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient intratumoral infiltration of cytotoxic T lymphocytes(CTLs)and the accumulation of immunosuppressive cells.Herein,we designed a lenvatinib-and vadimezan-loaded synthetic high-density lipoprotein(LV-sHDL)for combinational immunochemotherapy of metastatic TNBC.The LV-sHDL targeted scavenger receptor class B type 1-overexpressing 4T1 cells in the tumor after intravenous injection.The multitargeted tyrosine kinase inhibitor(TKI)lenvatinib induced immunogenic cell death of the cancer cells,and the stimulator of interferon genes(STING)agonist vadimezan triggered local inflammation to facilitate dendritic cell maturation and antitumor macrophage differentiation,which synergistically improved the intratumoral infiltration of total and active CTLs by 33-and 13-fold,respectively.LV-sHDL inhibited the growth of orthotopic 4T1 tumors,reduced pulmonary metastasis,and prolonged the survival of animals.The efficacy could be further improved when LV-sHDL was used in combination with antibody against programmed cell death ligand 1.This study highlights the combination use of multitargeted TKI and STING agonist a promising treatment for metastatic TNBC.

关键词： high-density lipoprotein Immunotherapy Combination therapy Metastasis Triple-negative breast cancer Lenvatinib Vadimezan Immune checkpoint blockad

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high-density lipoprotein associated factors apoA-I and serum amyloid A in Chinese non-diabetic patients with coronary heart disease

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Chinese Medical Journal 2010年第6期123卷 658-663页

作者： CHEN Guo-liang LIU Li-wei XIE Shuang LIU Hong LIU Yu-qing LI Yi-shi Key Laboratory of Clinical Trial Research in Cardiovascular Drug Ministry of HealthCardiovascular Institute and Fu Wai HospitalPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100037China

Background high-density lipoprotein cholesterol（HDL-C）levels are a strong,independent inverse predictor of coronary heart disease （CHD）.In this cross-sectional study we investigated the interrelationships between HDL-C and HDL relaled factors apolipoprotein A-I（apoA-I）and serum amyloid A（SAA）and the presence and extent of CHD in a population of Chinese patients with CHD. Methods Two hundred and twenty-four consecutive patients took part in this study.Demographic data were obtained from hospital records.Serum chemical concentrations were measured by standard laboratory methods.Reaults The concentrations of high-sensitive C-reactive protein（hsCRP）（median：1.85 mg/L）and SAP,（median：9.40 mg/L）were significantly higher in the CHD group（P〈0.05）,while concentrations of HDL-C（0.03±0.25）mmol/L）and apoA-I（（604.59±1 05.79）mmol/L）were significantly lower than those in the non-CHD group（P〈0.05）.The concentrations of apoA-l decreased with the increase in vascular damage.but the difference did not reach statistical significance.However, the concentrations of hsCRP and SAA increased with the increase in vascular damage.The unadjusted odd ratios（ORs）（CI） for apoA-I and SAA of the presence of CHD were 0.093（0.990-0.997）（P=0.00）and 2.571（1.029-6.424）（P〈0.05）,respectively.The association between elevated SAA and the presence of CHD was lost after adjusting for lipid status parameter concentrations.The associations between apoA-I.SAA and the extent of CHD remained strong,regardless of confounding variables.Conclusions Increased concentrations of SAA represent the inflammatory marker of the extent of coronary stenosis in patients with CHD.In contrast to SAA, the level of apoA-I was also associated with the presence of CHD, indicating that apoA-I was not only a marker of CHD presence but also a quantitative indicator of CHD extent.In short.determining the change apolipoprotein content within HDL particle is a more accurate and effective method to evaluate the impact of HDL on CHD.

关键词： high-density lipoprotein apolipoprotein A-I serum amyloid A coronary heart disease

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Effect of low high-density lipoprotein levels on mortality of septic patients: A systematic review and meta-analysis of cohort studies

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World Journal of Emergency Medicine 2020年第2期11卷 109-116页

作者： Shao-hua Liu Huo-yan Liang Hong-yi Li Xian-fei Ding Tong-wen Sun Jing Wang General ICU the First Affi liated Hospital of Zhengzhou UniversityHenan Key Laboratory of Critical Care MedicineZhengzhou 450052China Department of Respiratory Critical Care Medicine the First Affi liated Hospital of Zhengzhou UniversityZhengzhou 450052China

BACKGROUND:An increase in high-density lipoprotein(HDL)is well associated with a decreased cardiovascular risk,especially atherosclerosis.Recent studies suggest that lower levels of HDL may also be associated with an increased risk of sepsis and an increased rate of mortality in septic patients.However,this conclusion remains controversial.METHODS:MEDLINE,EMBASE,and CENTRAL databases were searched from inception to September 30,2019.All studies were conducted to evaluate the correlation of lipoprotein levels and the risk and outcomes of sepsis in adult patients.The primary outcomes were the risk and mortality of sepsis.RESULTS:Seven studies comprising 791 patients were included.Lower levels of HDL had no marked relevance with the risk of sepsis(odds radio[OR]for each 1 mg/dL increase,0.94;95%CI 0.86–1.02;P=0.078),whereas lower HDL levels were related to an increased mortality rate in septic patients(OR for below about median HDL levels,2.00;95%CI 1.23–3.24;P=0.005).CONCLUSION:This meta-analysis did not reveal a signifi cant association between lower HDL levels and an increase in the risk of sepsis,whereas it showed that lower HDL levels are associated with a higher mortality rate in septic adult patients.These findings suggest that HDL may be considered as a promising factor for the prevention and treatment of sepsis in the future.

关键词： high-density lipoprotein Sepsis Mortality Meta-analysis

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high density lipoprotein suppresses lipoprotein associated phospholipase A2 in human monocytes-derived macrophages through peroxisome proliferator-activated receptor-γ pathway

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Chinese Medical Journal 2012年第24期125卷 4474-4480页

作者： HAN Guan-ping REN Jing-yi QIN Li SONG Jun-xian WANG Lan CHEN Hong Department of Cardiology Peking University People's Hospital Beijing 100044 China Department of Laboratory Medicine Peking University People's Hospital Beijing 100044 China

Background lipoprotein-associated phospholipase A2 （Lp-PLA2） is mainly secreted by macrophages, serving as a specific marker of atherosclerotic plaque and exerting pro-atherogenic effects. It is known that high-density lipoprotein （HDL） plays an important role against atherosclerosis by inhibiting pro-inflammatory factors, however, the relationship between HDL and Lp-PLA2 remains elusive. Methods In this study, reverse transcription-polymerase chain reaction （RT-PCR）, Western blotting, and a platelet-activating factor （PAF） acetylhydrolase assay were performed to determine the Lp-PLA2 mRNA level, protein expression and activity in human monocyte-derived macrophages upon HDL treatment of different concentrations and durations. To investigate the underlying mechanism of HDL-induced Lp-PLA2 action, pioglitazone, a peroxisome proliferator-activated receptor-γ （PPARy） ligand, was introduced to human monocyte-derived macrophages and mRNA and protein levels of Lp-PLA2, as well as its activity, were determined. Results Lp-PLA2 mRNA levels, protein expression and activity were significantly inhibited in response to HDL treatment in a dose and time dependent manner in human monocyte-derived macrophages. Pioglitazone treatment （1-10 ng/ml） upregulated the Lp-PLA2 mRNA level, protein expression and activity in human monocyte-derived macrophages, while the effects were markedly reversed by HDL. In addition, pioglitazone resulted in a significant increase in PPARy phosphorylation in human monocyte-derived macrophages, which could be inhibited by HDL. Conclusion These findings indicate that HDL suppresses the expression and activity of Lp-PLA2 in human monocyte-derived macrophages, and the underlying mechanisms may be mediated through the PPARγ pathway.

关键词： atherosclerosis high-density lipoprotein lipoprotein-associated phospholipase A2 peroxisome proliferator-activated receptor-γ

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The relationship between serum amyloid A and apolipoprotein A-I in high-density lipoprotein isolated from patients with coronary heart disease

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Chinese Medical Journal 2013年第19期126卷 3656-3661页

作者： WANG Dong-xue LIU Hong YAN Li-rong ZHANG Ye-ping GUAN Xiao-yuan XU Zhi-min JIA You-hong LI Yi-shi zKey Laboratory of Clinical Trial Research in Cardiovascular Drugs Ministry of Health State Key Laboratory of Cardiovascular DiseasesFuwai Hospital National Center for Cardiovascular DiseasesPeking Union Medical College and Chinese Academy of MedicalSciences Beijing 100037China

Background Alteration in the protein composition of high-density lipoprotein （HDL） has been proposed as a mechanism for the development of coronary heart disease （CHD）.In HDL,an increase in serum amyloid A protein （SAA） accompanying the decrease in apolipoprotein A-I （apoA-I） has been found during the acute inflammation period.However,whether this phenomenon persists in CHD patients,a disease related to inflammation,is unknown.The purpose of the present study was to explore the relationship between SAA and apoA-I in HDL isolated from CHD patients.Methods Overall,98 patients with confirmed stable CHD and 90 control subjects matched for age and gender were enrolled in this case-control study.Potassium bromide （KBr） density gradient ultracentrifugation was used to isolate HDL from plasma.The levels of SAA and apoA-I in the HDL samples were detected by enzyme-linked immunosorbent assay kits.Pearson＇s correlation and general linear models were used in the analysis.Results Compared with controls,patients with CHD had a significant decrease in the amount of apoA-I （（14.21±8.44） μg/ml vs.（10.95±5.95） μg/ml,P =0.003） in HDL and a significant increase in the amount of log SAA （1.21±0.46 vs.1.51±0.55,P 〈0.00001）.Differences were independent of age,body mass index （BMI）,HDL cholesterol （HDL-C）,and other factors.An independently and statistically significant positive correlation between log SAA and apoA-I in HDL was observed only in the CHD group （β =2.0,P =0.026）.In the general linear model,changes in Iog（SAA）,age,age2,gender,BMI and HDL-C could explain a statistically significant 43% of the variance in apoA-I.Conclusions This study provides direct evidence for the first time that there was an independent positive correlation between log SAA and apoA-I in the HDL of CHD patients,indicating the alteration of protein composition in HDL.However,the question of whether this alteration in HDL is associated with impairment of HDL functions requires further research.

关键词： coronary heart disease lipoproteins high-density lipoprotein serum amyloid A protein apolipoprotein A-I

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high-density lipoprotein mimetic nanotherapeutics for cardiovascular and neurodegenerative diseases

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Nano Research 2018年第10期11卷 5130-5143页

作者： Song Ih Ahn Hyun-Ji Park diwon Yom Taeyoung Kim YongTae Kim George W. Woodruff School of Mechanical Engineering Georgia Institute of Technology Atlanta GA 30332 USA Parker H. Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology Atlanta GA 30332 USA Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology Atlanta GA 30332 USA Institute for Electronics and Nanotechnology Georgia Institute of Technology Atlanta GA 30332 USA

high-density lipoprotein （HDL） serves as a natural nanoparticle with compositional and functional heterogeneity and contributes to the maintenance of lipid metabolism and various biological functions. HDL also transports endogenous microRNAs, vitamins, hormones, and proteins through blood and interstitial fluids to various organs. These unique and diverse features of HDL have encouraged its applications for the transport of therapeutics and diagnostic reagents in the last decade. In this review, we describe the heterogeneous characteristics and biological functions of HDL and highlight HDL mimetic approaches, including apolipoprotein mimetic peptides and reconstituted HDL nanoparticles. Given the potential of HDL as a nanocarrier delivering various therapeutic agents, we discuss the current representative studies of HDL mimetic nanotherapeutics for cardiovascular and neurodegenerative diseases and analyze the current challenges and future perspective.

关键词： high-density lipoprotein nanotherapeutic cardiovascular disease neurodegenerative disease

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Glycation of high-density lipoprotein in type 2 diabetes mellitus

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Chinese Medical Journal 2013年第21期126卷 4162-4165页

作者： Sun Jia-teng Shen Ying Lu An-kang Lu Lin Shen Wei-feng Shanghai Jiao Tong Univ Sch Med Dept Cardiol Ruijin Hosp Shanghai 200025 Peoples R China Shanghai Jiao Tong Univ Sch Med Inst Cardiovasc Dis Shanghai 200025 Peoples R China

Objective To evaluate whether glycation of high-density lipoprotein （HDL） increases cardiovascular risk in patients with type 2 diabetes mellitus by altering its anti-atherogenic property.

关键词： glycation high-density lipoprotein atherosclerosis diabetes

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The New Strategy for Modulating Dyslipidemia:Consideration from Updated Understanding on high-density lipoprotein

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Chinese Journal of Integrative Medicine 2011年第6期17卷 467-470页

作者：文川徐浩 National Integrative Medicine Center for Cardiovascular Diseases China-Japan Friendship Hospital National Integrative Medicine Center for Cardiovascular Diseases China-Japan.Friendship Hospital

With further researches on blood lipids and atherosclerosis,especially after the conception of＂residual cardiovascular risk＂,high-density lipoprotein cholesterol（HDL-C） becomes a new therapeutic target against atherosclerosis.However,the failure of ILLUMINATE study that was targeted at raising HDL-C level disappointed cardiologists all over the world,which indicates the limitation of HDL-C concentration in representing HDL function.The updated understanding of HDL from＂quantity＂to＂quality＂brings a new cut-in point for integrative Chinese and Western medicine in preventing and treating dyslipidemia and atherosclerosis. In addition to highlighting statins in directly intervening low-density lipoprotein cholesterol,we should make full use of the superiority of Chinese medicine in overall regulation and individualized treatment to promote the self-healing capacity of the patients,which further regulates abnormity of both concentration and function of the whole blood lipid family to equilibrium.This new strategy for modulating dyslipidemia with mutual complement of advantages from Western and Chinese medicines will no doubt play an important role in future therapies.

关键词： atherosclerosis high-density lipoprotein dyslipidemi integrative medicine

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Advances in studies on the regulation of periodontal disease by high-density lipoprotein

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Journal of Hainan Medical University 2020年第21期26卷 71-74页

作者： Zhu-Ling Guo Wan-Yun Lin Chen Xie Qi-Ya Fu Department of Stomatology The First Affiliated Hospital of Hainan Medical UniversityHaikou 570102PR China School of Stomatology Hainan Medical UniversityHaikou 570100PR China

Many studies in recent years have considered the potential relationship between periodontitis and lipid parameters.Currently,it is generally accepted that HDL(high-density lipoprotein)is one of the lipoproteins that play an important role in immunity and an important part of maintaining periodontal homeostasis.In this paper,the protective mechanism of HDL in periodontitis was discussed,and the adjuvant therapeutic effect of HDL in periodontitis with systemic disease was emphasized.

关键词： high-density lipoprotein Periodontitis Lipopolysaccharide

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