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Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRβ

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Frontiers of Medicine 2024年第3期18卷 465-483页

作者： Fei Xu Han Chen Changyi Zhou Tongtong Zang Rui Wang Shutong Shen Chaofu Li Yue Yu Zhiqiang Pei Li Shen Juying Qian Junbo Ge Department of cardiology and Laboratory of Heart Valve Disease West China HospitalSichuan UniversityChengdu610041China Department of cardiology Zhongshan HospitalFudan UniversityResearch Unit of Cardiovascular Techniques and DevicesChinese Academy of Medical SciencesShanghai200032China Shanghai Institute of cardiovascular Diseases Shanghai200032China National Clinical Research Center for Interventional Medicine&Shanghai Clinical Research Center for Interventional Medicine(19MC1910300) Shanghai200032China

Atherosclerosis is a chronic artery disease that causes various types of cardiovascular *** smooth muscle cells(VSMCs),the main components of atherosclerotic plaque,switch from contractile to synthetic phenotypes during *** is crucial in regulating VSMC phenotypes in atherosclerosis,and it can be reversely regulated by ***,the specific effects of deubiquitinases on atherosclerosis have not been thoroughly *** this study,RNAi screening in human aortic smooth muscle cells was performed to explore the effects of OTU family deubiquitinases,which revealed that silencing OTUB1 inhibited PDGF-BB-stimulated VSMC phenotype *** in vivo studies using Apoe−/−mice revealed that knockdown of OTUB1 in VSMCs alleviated atherosclerosis plaque burden in the advanced stage and led to a stable plaque ***,VSMC proliferation and migration upon PDGF-BB stimulation could be inhibited by silencing OTUB1 in *** RNA-sequencing data indicated that knocking down OTUB1 influenced VSMC differentiation,adhesion,and *** spectrometry of ubiquitinated protein confirmed that proteins related to cell growth and migration were differentially ***,we found that OTUB1 recognized the K707 residue ubiquitylation of PDGFRβwith its catalytic triad,thereby reducing the K48-linked ubiquitylation of PDGFRβ.Inhibiting OTUB1 in VSMCs could promote PDGFRβdegradation via the ubiquitin–proteasome pathway,so it was beneficial in preventing VSMCs’phenotype *** findings revealed that knocking down OTUB1 ameliorated VSMCs’phenotype switch and atherosclerosis progression,indicating that OTUB1 could be a valuable translational therapeutic target in the future.

关键词： atherosclerosis vascular smooth muscle cell ubiquitylation deubiquitinase OTUB1 PDGFRβ

Macrophages in cardiovascular diseases:molecular mechanisms and therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2598-2641页

作者： Runkai Chen Hongrui Zhang Botao Tang Yukun Luo Yufei Yang Xin Zhong Sifei Chen Xinjie Xu Shengkang Huang Canzhao Liu Department of cardiology Laboratory of Heart CenterHeart CenterTranslational Medicine Research CenterZhujiang HospitalSouthern Medical University253 Industrial AvenueGuangzhou 510280China State Key Laboratory of cardiovascular Disease Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China

The immune response holds a pivotal role in cardiovascular disease *** multifunctional cells of the innate immune system,macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury,thereby inducing subsequent damage while also facilitating ***,the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases,including coronary heart disease,valvular disease,myocarditis,cardiomyopathy,heart failure,atherosclerosis and aneurysm,which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific ***,recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity,cell–cell interactions,and downstream mechanisms of therapeutic targets at a higher resolution,which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular ***,myocardial fibrosis,a prevalent characteristic in most cardiac diseases,remains a formidable clinical challenge,necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac *** this review,we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by singlecell sequencing technologies,with a focus on different causes and characteristics of diseases,especially the relationship between inflammation and fibrosis in cardiac diseases(myocardial infarction,pressure overload,myocarditis,dilated cardiomyopathy,diabetic cardiomyopathy and cardiac aging)and the relationship between inflammation and vascular injury in vascular diseases(atherosclerosis and aneurysm).Finally,we also highlight the preclinical/clinical macrophage targeting strategies and translational

关键词： diseases cardiovascular therapeutic

Therapeutic advances in atrial fibrillation based on animal models

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第2期25卷 135-152页

作者： Qian GONG Xuan LE Pengcheng YU Lenan ZHUANG Institute of Genetics and Reproduction College of Animal SciencesZhejiang UniversityHangzhou310058China Key Laboratory of cardiovascular Intervention and Regenerative Medicine of Zhejiang Province Department of CardiologySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China

Atrial fibrillation(AF)is the most prevalent sustained cardiac arrhythmia among humans,with its incidence increasing significantly with *** the high frequency of AF in clinical practice,its etiology and management remain *** develop effective treatment strategies,it is imperative to comprehend the underlying mechanisms of AF;therefore,the establishment of animal models of AF is vital to explore its *** spontaneous AF is rare in most animal species,several large animal models,particularly those of pigs,dogs,and horses,have proven as invaluable in recent years in advancing our knowledge of AF pathogenesis and developing novel therapeutic *** review aims to provide a comprehensive discussion of various animal models of AF,with an emphasis on the unique features of each model and its utility in AF research and *** data summarized in this review provide valuable insights into the mechanisms of AF and can be used to evaluate the efficacy and safety of novel therapeutic interventions.

关键词： Atrial fibrillation Animal model Therapeutic

Plasma metabolites and risk of myocardial infarction:a bidirectional Mendelian randomization study

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Journal of Geriatric cardiology 2024年第2期21卷 219-231页

作者： Dong-Hua LI Qiang WU Jing-Sheng LAN Shuo CHEN You-Yi HUANG Lan-Jin WU Zhi-Qing QIN Ying HUANG Wan-Zhong HUANG Ting ZENG Xin HAO Hua-Bin SU Qiang SU Department of cardiovascular Medicine Minzu Hospital of Guangxi Zhuang Autonomous RegionGuangxiChina Senior Department of cardiology the Sixth Medical CenterChinese PLA General HospitalBeijingChina Library of graduate School Chinese PLA General HospitalBeijingChina Department of cardiology Jiangbin Hospital of Guangxi Zhuang Autonomous RegionGuangxiChina Health Management Institute the Second Medical CenterChinese PLA General HospitalBeijingChina

BACKGROUND Myocardial infarction(MI)is a critical cardiovascular event with multifaceted etiology,involving several genetic and environmental *** is essential to understand the function of plasma metabolites in the development of MI and unravel its complex *** This study employed a bidirectional Mendelian randomization(MR)approach to investigate the causal relationships between plasma metabolites and MI *** used genetic instruments as proxies for plasma metabolites and MI and conducted MR analyses in both directions to assess the impact of metabolites on MI risk and vice *** addition,the large-scale genome-wide association studies datasets was used to identify genetic variants associated with plasma metabolite(1400 metabolites)and MI(20,917 individuals with MI and 440,906 individuals without MI)*** variance weighted was the primary method for estimating causal *** estimates are expressed as beta coefficients or odds ratio(OR)with 95%*** We identified 14 plasma metabolites associated with the occurrence of MI(P<0.05),among which 8 plasma metabolites[propionylglycine levels(OR=0.922,95%CI:0.881–0.965,P<0.001),gamma-glutamylglycine levels(OR=0.903,95%CI:0.861–0.948,P<0.001),hexadecanedioate(C16-DC)levels(OR=0.941,95%CI:0.911–0.973,P<0.001),pentose acid levels(OR=0.923,95%CI:0.877–0.972,P=0.002),X-24546 levels(OR=0.936,95%CI:0.902–0.971,P<0.001),glycine levels(OR=0.936,95%CI:0.909–0.964,P<0.001),glycine to serine ratio(OR=0.930,95%CI:0.888–0.974,P=0.002),and mannose to trans-4-hydroxyproline ratio(OR=0.912,95%CI:0.869–0.958,P<0.001)]were correlated with a decreased risk of MI,whereas the remaining 6 plasma metabolites[1-palmitoyl-2-arachidonoyl-GPE(16:0/20:4)levels(OR=1.051,95%CI:1.018–1.084,P=0.002),behenoyl dihydrosphingomyelin(d18:0/22:0)levels(OR=1.076,95%CI:1.027–1.128,P=0.002),1-stearoyl-2-docosahexaenoyl-GPE(18:0/22:6)levels(OR=1.067,95%CI:1.027–1.109,P=0.001),alpha-ketobutyrate levels(OR=1.108,95%

关键词： infarction alterations diagnosis

Associations between remnant cholesterol levels and mortality in patients with diabetes

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World Journal of Diabetes 2024年第4期15卷 712-723页

作者： Deng Pan Lin Xu Li-Xiao Zhang Da-Zhuo Shi Ming Guo Department of cardiovascular Xiyuan Hospital of China Academy of Chinese Medical SciencesBeijing 100091China graduate School Beijing University of Chinese MedicineBeijing 100020China National Clinical Research Center for Chinese Medicine cardiology Xiyuan Hospital of China Academy of Chinese Medical SciencesBeijing 100091China Gynecological Department of Traditional Chinese Medicine China-Japan Friendship HospitalBeijing 100020China

BACKGROUND Dyslipidemia is frequently present in patients with *** associations of remnant cholesterol and mortality remains unclear in patients with *** To explore the associations of remnant cholesterol with all-cause and cardiovas-cular mortality in patients with *** This prospective cohort study included 4740 patients with diabetes who par-ticipated in the National Health and Nutrition Examination Survey from 1999 through *** cholesterol was used as the exposure variable,and all-cause and cardiovascular mortality were considered outcome *** data were obtained from the National Death Index,and all participants were followed from the interview date until death or December 31,*** proportional Cox regression models were used to explore the associations between exposure and outcomes,in which remnant cholesterol was modeled as both a categorical and a continuous *** cubic splines(RCSs)were calculated to assess the nonlinearity of ***(stratified by sex,age,body mass index,and duration of diabetes)and a series of sensitivity analyses were performed to evaluate the robustness of the *** During a median follow-up duration of 83 months,1370 all-cause deaths and 389 cardiovascular deaths were *** with remnant cholesterol levels in the third quartile had a reduced risk of all-cause mortality[hazard ratio(HR)95%confidence interval(CI):0.66(0.52-0.85)];however,when remnant cholesterol was modeled as a continuous variable,it was associated with increased risks of all-cause[HR(95%CI):1.12(1.02-1.21)per SD]and cardiovascular[HR(95%CI):1.16(1.01-1.32),per SD]*** RCS demonstrated nonlinear associations of remnant cholesterol with all-cause and cardiovascular *** and sensitivity analyses did not reveal significant differences from the above *** In patients with diabetes,higher remnant cholesterol was associated wi

关键词： Diabetes Remnant cholesterol Mortality cardiovascular National Health and Nutrition Examination Survey

Transient induction of actin cytoskeletal remodeling associated with dedifferentiation,proliferation,and redifferentiation stimulates cardiac regeneration

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2537-2553页

作者： Wenbin Fu Qiao Liao Yu Shi Wujian Liu Hongmei Ren Chunmei Xu Chunyu Zeng Department of cardiology Daping Hospitalthe Third Military Medical University(Army Medical University)Chongqing 400042China Key Laboratory of Geriatric cardiovascular and Cerebrovascular Disease Research Ministry of Education of ChinaChongqing 400042China Chongqing Key Laboratory for Hypertension Research Chongqing Cardiovascular Clinical Research CenterChongqing Institute of CardiologyChongqing 400042China State Key Laboratory of Trauma Burns and Combined InjuryDaping Hospitalthe Third Military Medical UniversityChongqing 400042China cardiovascular Research Center Chongqing CollegeUniversity of Chinese Academy of SciencesChongqing 400042China State Key Laboratory of Trauma and Chemical Poisoning Chongqing 400042China

The formation of new and functional cardiomyocytes requires a 3-step process:dedifferentiation,proliferation,and redifferentiation,but the critical genes required for efficient dedifferentiation,proliferation,and redifferentiation remain *** our study,a circular trajectory using single-nucleus RNA sequencing of the pericentriolar material 1 positive(PCM1^(+))cardiomyocyte nuclei from hearts 1 and 3 days after surgery-induced myocardial infarction(MI)on postnatal Day 1 was reconstructed and demonstrated that actin remodeling contributed to the dedifferentiation,proliferation,and redifferentiation of cardiomyocytes after *** identified four top actin-remodeling regulators,namely Tmsb4x,Tmsb10,Dmd,and Ctnna3,which we collectively referred to as *** expressed changes of 2D2P,using a polycistronic non-integrating lentivirus driven by Tnnt2(cardiac-specific troponin T)promoters(Tnnt2-2D2P-NIL),efficiently induced transiently proliferative activation and actin remodeling in postnatal Day 7 cardiomyocytes and adult ***,the intramyocardial delivery of Tnnt2-2D2P-NIL resulted in a sustained improvement in cardiac function without ventricular dilatation,thickened septum,or fatal arrhythmia for at least 4 *** conclusion,this study highlights the importance of actin remodeling in cardiac regeneration and provides a foundation for new gene-cocktail-therapy approaches to improve cardiac repair and treat heart failure using a novel transient and cardiomyocyte-specific viral construct.

关键词： Single cell analysis Actin remodeling Tmsb4x Tmsb10 Dmd Ctnna3 Myocardial infarction Cardiomyocytes proliferation Cardiac regeneration Genetic therapy

Dysregulated microRNAs in type 2 diabetes and breast cancer:Potential associated molecular mechanisms

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World Journal of Diabetes 2024年第6期15卷 1187-1198页

作者： Alex Cleber Improta-Caria Filipe Ferrari João Lucas Penteado Gomes Paloma Brasilio Villalta Úrsula Paula RenóSoci Ricardo Stein Edilamar M Oliveira Laboratory of Biochemistry and Molecular Biology of the Exercise Physical Education and Sport SchoolUniversity of São PauloSão Paulo 05508-030Brazil graduate program in cardiology and cardiovascular sciences Federal University of Rio Grande do SulHospital de Clínicas de Porto AlegrePorto Alegre 90035003Brazil Laboratory of Metabolic Disorders(Labdime) School of Applied SciencesUniversity of Campinas-UNICAMPCampinas 13484-350Brazil Departments of Internal Medicine Molecular Pharmacology and PhysiologyCenter for Regenerative MedicineUSF Health Heart InstituteMorsani College of MedicineUniversity of South FloridaTampaFL 33602United States

Type 2 diabetes(T2D)is a multifaceted and heterogeneous syndrome associated with complications such as hypertension,coronary artery disease,and notably,breast cancer(BC).The connection between T2D and BC is established through processes that involve insulin resistance,inflammation and other *** this comprehension the specific cellular and molecular mechanisms linking T2D to BC,especially through microRNAs(miRNAs),remain *** are regulators of gene expression at the post-transcriptional level and have the function of regulating target genes by modulating various signaling pathways and biological ***,the signaling pathways and biological processes regulated by miRNAs that are associated with T2D and BC have not yet been *** review aims to identify dysregulated miRNAs in both T2D and BC,exploring potential signaling pathways and biological processes that collectively contribute to the development of BC.

关键词： Type 2 diabetes Breast cancer MicroRNAs Molecular mechanisms

残余胆固醇与心血管、癌症死亡率的相关性:一项全国性队列研究

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Science Bulletin 2024年第4期69卷 526-534页

作者：田原武依戚敏杰宋莉娟陈伯望王椿淇路甲鹏杨阳张小艳崔建兰许巍杨皓贺文彦张岩郑昕张海波郭远林李希 National Clinical Research Center of cardiovascular Diseases State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Henan Provincial Center for Disease Control and Prevention Zhengzhou 450000China Department of cardiology Fuwai HospitalNational Center for Cardiovascular DiseaseChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Shenzhen Center for cardiovascular Diseases Fuwai Hospital Chinese Academy of Medical SciencesShenzhen 501800China Central China Sub-Center of the National Center for cardiovascular Diseases Zhengzhou 450000China

The health significance of triglyceride-rich lipoproteins,also known as remnant cholesterol,has been increasingly ***,evidence of their associations with cause-specific mortality in the general population was previously *** explore these associations and their heterogeneities across subgroups,a prospective cohort study was conducted including 3,403,414 community-based participants from China HEART,an ongoing government-funded public health program throughout China,from November 2014 through December *** study assessed mortality risk of all-cause mortality,cardiovascular disease(CVD)mortality(including mortality from ischemic heart diseases(IHD),ischemic stroke(IS),and hemorrhagic stroke(HS),separately),and cancer mortality(including lung cancer,stomach cancer,and liver cancer,separately).During the 4-year follow-up,23,646 individuals died from CVD(including 8807 from IHD,3067 from IS,and 5190 from HS),and 20,318 from cancer(including 6208 from lung cancer,3013 from liver cancer,and 2174 from stomach cancer).Compared with individuals with remnant cholesterolcardiovascular disease mortality,as well as a reduced risk of mortality for certain types of cancer.

关键词： Remnant cholesterol Mortality cardiovascular disease Cancer

Maternal Preconception Serum Alanine Aminotransferase Levels and Risk of Preterm Birth among Reproductive-Aged Women—China,2013-2017

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China CDC weekly 2024年第10期6卷 181-188,I0001页

作者： Chuanyu Zhao Jiajing Jia Hanbin Wu Qin Xu Xinyi Lyu Meiya Liu Xuan Hu Jueming Lei Yuzhi Deng Yuan He Yuanyuan Wang Zuoqi Peng Ya Zhang Hongguang Zhang Qiaomei Wang Haiping Shen Yiping Zhang Donghai Yan Ying Yang Xu Ma National Research Institute for Family Planning BeijingChina National Human Genetic Resources Center BeijingChina graduate School of Peking Union Medical College BeijingChina Department of Epidemiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Summary What is already known about this topic?The significance of maternal liver health concerning preterm birth(PTB)is well recognized;however,there is a gap in understanding the precise influence of preconception s... 详细信息

关键词： Serum precise concerning