Advertisement

Low-density lipoprotein receptor and apolipoprotein A 5, myocardial infarction biomarkers in plasma-derived exosomes

  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors
    Yue He
    Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors
    Affiliations
    Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors
    Xinsheng Gu
    Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors
    Affiliations
    Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors
    Ying Hu
    Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors
    Affiliations
    Department of Geriatric Medicine, Shanghai Xuhui District Central Hospital, Shanghai, China
    Search for articles by this author
  • Hao Jia
    Affiliations
    The First Department of Medical Affairs, Affiliated Renji Hospital, Shanghai JiaoTong University, Shanghai, China
    Search for articles by this author
  • Zhibo Zhao
    Affiliations
    Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, China
    Search for articles by this author
  • Haisong Jiang
    Correspondence
    Corresponding author at: Institute of Neurology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China.
    Affiliations
    Institute of Neurology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
    Search for articles by this author
  • Hongchao Zheng
    Correspondence
    Corresponding author at: Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, 200031, China.
    Affiliations
    Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, China
    Search for articles by this author
  • Fu Zhu
    Correspondence
    Corresponding author at: Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, 200031, China.
    Affiliations
    Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and should be considered co-first authors
Published:January 17, 2022DOI:https://doi.org/10.1016/j.jjcc.2021.10.020

      Highlights

      • Low-density lipoprotein receptor (LDLR) and apolipoprotein A V are associated with myocardial infarction (MI).
      • Both were decreased in exosomes of MI patients.
      • Exosomes of MI patients were larger and more concentrated than that of controls.
      • Exosomes rescued the reduction of LDLR expression in cardiomyocytes caused by oxygen-glucose deprivation.

      Abstract

      Objectives

      Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. Previously, rare mutations in low-density lipoprotein receptor (LDLR) genes and apolipoprotein A V (APOA5) have been shown to contribute to MI risk in individual families. Exosomes provide a potential source of biomarkers for MI. This study is to determine the role of LDLR and APOA5 as biomarkers for early diagnosis of MI.

      Methods

      In this study, we detected the levels of LDLR, APOA5, and cardiac troponin T in plasma-derived exosomes in MI patients and age-matched healthy people by enzyme linked immunosorbent assay and observed the morphology and number of exosomes using transmission electron microscope and nanoparticle tracking analysis. Oxygen-glucose deprivation (OGD) method was used to induce MI in H9C2 cardiomyocytes to explore the effect of exosomes.

      Results

      We found that the levels of LDLR and APOA5 in plasma-derived exosomes in MI patients were significantly decreased. Furthermore, exosomes of MI patients were significantly larger in size and the concentration of exosomes was higher than that of age-matched non-MI people. In vitro experiments showed that OGD treatment induced apoptosis of myocardial cells and decreased the expression of LDLR and APOA5, while addition of exosomes isolated from healthy people rescued these phenotypes.

      Conclusion

      Exosomal APOA5 and LDLR are intimately associated with MI, and thereby have the potential to function as diagnostic markers of MI.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Zhou Y
        • Yao X
        • Liu G
        • Jian W
        • Yip W.
        Level and variation on quality of care in China: a cross-sectional study for the acute myocardial infarction patients in tertiary hospitals in Beijing.
        BMC Health Serv Res. 2019; 19: 43
        • Zhang Q
        • Zhao D
        • Xie W
        • Xie X
        • Guo M
        • Wang M
        • et al.
        Recent trends in hospitalization for acute myocardial infarction in Beijing: increasing overall burden and a transition from ST-segment elevation to non-ST-segment elevation myocardial infarction in a population-based study.
        Medicine (Baltimore). 2016; 95: e2677
        • Titov BV
        • Osmak GJ
        • Matveeva NA
        • Kukava NG
        • Shakhnovich RM
        • Favorov AV
        • et al.
        Genetic risk factors for myocardial infarction more clearly manifest for early age of first onset.
        Mol Biol Rep. 2017; 44: 315-321
        • Fischer M
        • Broeckel U
        • Holmer S
        • Baessler A
        • Hengstenberg C
        • Mayer B
        • et al.
        Distinct heritable patterns of angiographic coronary artery disease in families with myocardial infarction.
        Circulation. 2005; 111: 855-862
        • Roberts R.
        Genetics of premature myocardial infarction.
        Genetics. 2008; 10: 186-193
        • Elkins JC
        • Fruh S.
        Early diagnosis and treatment of familial hypercholesterolemia.
        Nurse Pract. 2019; 44: 18-24
        • Do R
        • Stitziel NO
        • Won H
        • Jørgensen AB
        • Duga S
        • Merlini PA
        • et al.
        Multiple rare alleles at LDLR and APOA5 confer risk for early-onset myocardial infarction.
        Nature. 2015; 518: 102-106
        • Norata GD
        • Tsimikas S
        • Pirillo A
        • Catapano AL.
        Apolipoprotein C-III: From pathophysiology to pharmacology.
        Trends Pharmacol Sci. 2015; 36: 675-687
        • Sharma V
        • Forte TM
        • Ryan RO.
        Influence of apolipoprotein A-V on the metabolic fate of triacylglycerol.
        Curr Opin Lipidol. 2013; 24: 153-159
        • Mega JL
        • Stitziel NO
        • Smith JG
        • Chasman DI
        • Caulfield M
        • Devlin JJ
        • et al.
        Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.
        Lancet. 2015; 385: 2264-2271
        • Nilsson SK
        • Christensen S
        • Raarup MK
        • Ryan RO
        • Nielsen MS
        • Olivecrona G.
        Endocytosis of apolipoprotein A-V by members of the low density lipoprotein receptor and the VPS10p domain receptor families.
        J Biol Chem. 2008; 283: 25920-25927
        • Nilsson SK
        • Lookene A
        • Beckstead JA
        • Gliemann J
        • Ryan RO
        • Olivecrona G.
        Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family.
        Biochemistry. 2007; 46: 3896-3904
        • Tan KH
        • Tan SS
        • Sk Sze
        • Lee WK
        • Ng MJ
        • Lim SK.
        Plasma biomarker discovery in in preeclampsia using a novel differential isolation technology for circulating extracellular vesicles.
        Am J Obstet Gynecol. 2014; 211: 380.e1-380.e13
        • Pienimaeki-Roemer A
        • Kuhlmann K
        • Böttcher A
        • Konovalova T
        • Black A
        • Orsó E
        • et al.
        Lipidomic and proteomic characterization of platelet extracellular vesicle subfractions from senescent platelets.
        Transfusion. 2015; 55: 507-521
        • Gao F
        • Jiao F
        • Xia C
        • Zhao Y
        • Ying W
        • Xie Y
        • et al.
        A novel strategy for facile serum exosome isolation based on specific interactions between phospholipid bilayers and TiO2.
        Chem Sci. 2018; 10: 1579-1588
        • Johnstone RM
        • Bianchini A
        • Teng K.
        Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions.
        Blood. 1989; 74: 1844-1851
        • Sohn W
        • Kim J
        • Kang SH
        • Yang SR
        • Cho J-Y
        • Cho HC
        • et al.
        Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma.
        Exp Mol Med. 2015; 47: e184
        • Nair S
        • Tang KD
        • Kenny L
        • Punyadeera C.
        Salivary exosomes as potential biomarkers in cancer.
        Oral Oncol. 2018; 84: 31-40
        • Manca S
        • Upadhyaya B
        • Mutai E
        • Desaulniers AT
        • Cederberg RA
        • White BR
        • et al.
        Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns.
        Sci Rep. 2018; 8: 11321
        • Ma B
        • Jiang H
        • Jia J
        • Di L
        • Song G
        • Jing Y
        • et al.
        Murine bone marrow stromal cells pulsed with homologous tumor-derived exosomes inhibit proliferation of liver cancer cells.
        Clin Transl Oncol. 2012; 14: 764-773
        • Zhan Y
        • Du L
        • Wang L
        • Jiang X
        • Zhang S
        • Li J
        • et al.
        Expression signatures of exosomal long non-coding RNAs in urine serve as novel non-invasive biomarkers for diagnosis and recurrence prediction of bladder cancer.
        Mol Cancer. 2018; 17 (29): 142
        • Kogure T
        • Lin WL
        • Yan IK
        • Braconi C
        • Patel T.
        Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth.
        Hepatology. 2011; 54: 1237-1248
        • Kanninen KM
        • Bister N
        • Koistinaho J
        • Malm T.
        Exosomes as new diagnostic tools in CNS diseases.
        Biochim Biophys Acta. 2016; 1862: 403-410
        • Gao XJ
        • Yang JG
        • Yang YJ
        • Li W
        • Xu HY
        • Wu Y
        • et al.
        Age-related coronary risk factors in Chinese patients with acute myocardial infarction.
        Natl Med J China. 2016; 96: 3251-3256
        • Lee C
        • Cui Y
        • Song J
        • Li S
        • Zhang F
        • Wu M
        • et al.
        Effects of familial hypercholesterolemia-associated genes on the phenotype of premature myocardial infarction.
        Lipids Health Dis. 2019; 18: 95
        • Khera AV
        • Chaffin M
        • Zekavat SM
        • Collins RL
        • Roselli C
        • Natarajan P
        • et al.
        Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.
        Circulation. 2019; 139: 1593-1602
        • Fruchart-najib J
        • Bauge E
        • Niculescu LS
        • Pham T
        • Thomas B
        • Rommens C.
        Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5.
        Biochem Biophys Res Commun. 2004; 319: 397-404
        • Schaap FG
        • Rensen PC
        • Voshol PJ
        • Vrins C
        • van der Vliet HN
        • Chamuleau RA
        • et al.
        ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.
        J Biol Chem. 2004; 279: 27941-27947
        • Hubáček JA
        • Adámková V
        • Vrablík M
        • Kadlecová M
        • Zicha J
        • Kunes J
        • et al.
        Apolipoprotein A5 in health and disease.
        Physiol Res. 2009; 58: S101-S109
        • Barile L
        • Moccetti T
        • Marbán E
        • Vassalli G.
        Roles of exosomes in cardioprotection.
        Eur Heart J. 2017; 38: 1372-1379
        • Sahoo S
        • Losordo DW.
        Exosomes and cardiac repair after myocardial infarction.
        Circ Res. 2014; 114: 333-344
        • Pan W
        • Zhu Y
        • Meng X
        • Zhang C
        • Yang Y
        • Bei Y.
        Immunomodulation by exosomes in myocardial infarction.
        J Cardiovasc Transl Res. 2019; 12: 28-36
        • Murthy VV
        • Karmen A.
        Troponin-T as a serum marker for myocardial infarction.
        J Clin Lab Anal. 2015; 11: 125-128
        • Reichlin T
        • Hochholzer W
        • Bassetti S
        • Steuer S
        • Stelzig C
        • Hartwiger S
        • et al.
        Early diagnosis of myocardial infarction with sensitive cardiac troponin assays.
        N Engl J Med. 2009; 361: 858-867
        • Lim W
        • Qushmaq I
        • Deborah JC
        • Mark AC
        • Diane HA
        • Devereaux PJ.
        Elevated troponin and myocardial infarction in the intensive care unit: a prospective study.
        Crit Care. 2005; 9: R636-R644