Increased Expression of MiR-224-5p in Circulating Extracellular Vesicles of Patients with Reduced Coronary Flow Reserve

Overview

Journal BMC Cardiovasc Disord

Publisher Biomed Central

Specialty Cardiology & Vascular Diseases

Date 2022 Jul 19

PMID 35850658

Authors

Kreema James

Paulina Bryl-Gorecka

Bjorn Olde

Olof Gidlof

Kristina Torngren

David Erlinge

Affiliations

Soon will be listed here.

Abstract

Background: Endothelial and microvascular dysfunction are pivotal causes of major adverse cardiac events predicted by coronary flow reserve (CFR). Extracellular Vesicles (EVs) have been studied extensively in the pathophysiology of coronary artery disease. However, little is known on the impact of the non-coding RNA content of EVs with respect to CFR.

Methods: We carried out a study among 120 patients divided by high-CFR and low-CFR to profile the miRNA content of circulating EVs.

Results: A multiplex array profiling on circulating EVs revealed mir-224-5p (p-value ≤ 0.000001) as the most differentially expressed miRNA in the Low-CFR group and showed a significantly independent relationship to CFR. Literature survey indicated the origin of the miR from liver cells and not of platelet, leukocyte, smooth muscle or endothelial (EC) origin. A q-PCR panel of the conventional cell type-EVs along with hepatic EVs showed that EVs from liver cells showed higher expression of the miR-224-5p. FACS analysis demonstrated the presence of liver-specific (ASGPR-1+/CD14-) EVs in the plasma of our cohort with the presence of Vanin-1 required to enter the EC barrier. Hepatic EVs with and without the miR-224-5p were introduced to ECs in-vitro, but with no difference in effect on ICAM-1 or eNOS expression. However, hepatic EVs elevated endothelial ICAM-1 levels per se independent of the miR-224-5p.

Conclusion: This indicated a role of hepatic EVs identified by the miR-224-5p in endothelial dysfunction in patients with Low CFR.

Citing Articles

The Role of Circulating Biomarkers in Patients with Coronary Microvascular Disease.

Quarta R, Martino G, Romano L, Lopes G, Greco F, Spaccarotella C Biomolecules. 2025; 15(2).

PMID: 40001480 PMC: 11853534. DOI: 10.3390/biom15020177.

Treatment with PCSK9 inhibitors influences microRNAs expression and changes of arterial wall properties: a randomized controlled trial.

Rehberger Likozar A, Levstek T, Karun T, Trebusak Podkrajsek K, Zupan J, Sebestjen M Eur J Med Res. 2025; 30(1):138.

PMID: 40001082 PMC: 11863757. DOI: 10.1186/s40001-025-02398-6.

Liquid Biopsy in the Clinical Management of Cancers.

Ho H, Chung K, Kan C, Wong S Int J Mol Sci. 2024; 25(16).

PMID: 39201281 PMC: 11354853. DOI: 10.3390/ijms25168594.

Discovery of circulating miRNAs as biomarkers of chronic Chagas heart disease via a small RNA-Seq approach.

Villar S, Herreros-Cabello A, Callejas-Hernandez F, Maza M, Del Moral-Salmoral J, Gomez-Montes M Sci Rep. 2024; 14(1):1187.

PMID: 38216639 PMC: 10786931. DOI: 10.1038/s41598-024-51487-9.

Emerging Evidence Linking the Liver to the Cardiovascular System: Liver-derived Secretory Factors.

Liu X, Shao Y, Han L, Zhang R, Chen J J Clin Transl Hepatol. 2023; 11(5):1246-1255.

PMID: 37577236 PMC: 10412704. DOI: 10.14218/JCTH.2022.00122.

References

Lonardo A, Sookoian S, Pirola C, Targher G . Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism. 2015; 65(8):1136-50. DOI: 10.1016/j.metabol.2015.09.017. View

Aschermann M, Sedlacek K, Aschermann O, Linhart A . [Molecular genetics of myocardial infarction]. Vnitr Lek. 2007; 53(4):348-53. View

Gidlof O, Andersson P, van der Pals J, Gotberg M, Erlinge D . Cardiospecific microRNA plasma levels correlate with troponin and cardiac function in patients with ST elevation myocardial infarction, are selectively dependent on renal elimination, and can be detected in urine samples. Cardiology. 2011; 118(4):217-26. DOI: 10.1159/000328869. View

Shi B, Abrams M, Sepp-Lorenzino L . Expression of asialoglycoprotein receptor 1 in human hepatocellular carcinoma. J Histochem Cytochem. 2013; 61(12):901-9. PMC: 3840742. DOI: 10.1369/0022155413503662. View

Bramos D, Ikonomidis I, Tsirikos N, Kottis G, Kostopoulou V, Pamboucas C . The association of coronary flow changes and inflammatory indices to ischaemia-reperfusion microvascular damage and left ventricular remodelling. Basic Res Cardiol. 2008; 103(4):345-55. DOI: 10.1007/s00395-008-0720-5. View

Parker G, Picut C . Liver immunobiology. Toxicol Pathol. 2005; 33(1):52-62. DOI: 10.1080/01926230590522365. View

Hosseinkhani B, van den Akker N, Molin D, Michiels L . (Sub)populations of extracellular vesicles released by TNF-α -triggered human endothelial cells promote vascular inflammation and monocyte migration. J Extracell Vesicles. 2020; 9(1):1801153. PMC: 7480596. DOI: 10.1080/20013078.2020.1801153. View

Nguyen M, Karunakaran D, Geoffrion M, Cheng H, Tandoc K, Matic L . Extracellular Vesicles Secreted by Atherogenic Macrophages Transfer MicroRNA to Inhibit Cell Migration. Arterioscler Thromb Vasc Biol. 2017; 38(1):49-63. PMC: 5884694. DOI: 10.1161/ATVBAHA.117.309795. View

Rezeli M, Gidlof O, Evander M, Bryl-Gorecka P, Sathanoori R, Gilje P . Comparative Proteomic Analysis of Extracellular Vesicles Isolated by Acoustic Trapping or Differential Centrifugation. Anal Chem. 2016; 88(17):8577-86. DOI: 10.1021/acs.analchem.6b01694. View

10.

Thery C, Witwer K, Aikawa E, Alcaraz M, Anderson J, Andriantsitohaina R . Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2019; 7(1):1535750. PMC: 6322352. DOI: 10.1080/20013078.2018.1535750. View

11.

Gidlof O, Sathanoori R, Magistri M, Faghihi M, Wahlestedt C, Olde B . Extracellular Uridine Triphosphate and Adenosine Triphosphate Attenuate Endothelial Inflammation through miR-22-Mediated ICAM-1 Inhibition. J Vasc Res. 2015; 52(2):71-80. DOI: 10.1159/000431367. View

12.

Jansen F, Nickenig G, Werner N . Extracellular Vesicles in Cardiovascular Disease: Potential Applications in Diagnosis, Prognosis, and Epidemiology. Circ Res. 2017; 120(10):1649-1657. DOI: 10.1161/CIRCRESAHA.117.310752. View

13.

Jansen F, Yang X, Baumann K, Przybilla D, Schmitz T, Flender A . Endothelial microparticles reduce ICAM-1 expression in a microRNA-222-dependent mechanism. J Cell Mol Med. 2015; 19(9):2202-14. PMC: 4568925. DOI: 10.1111/jcmm.12607. View

14.

Clark P, Manes T, Pober J, Kluger M . Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations. J Invest Dermatol. 2006; 127(4):762-74. DOI: 10.1038/sj.jid.5700670. View

15.

Teoh N, Ajamieh H, Wong H, Croft K, Mori T, Allison A . Microparticles mediate hepatic ischemia-reperfusion injury and are the targets of Diannexin (ASP8597). PLoS One. 2014; 9(9):e104376. PMC: 4164362. DOI: 10.1371/journal.pone.0104376. View

16.

Zhang H, Liu J, Qu D, Wang L, Wong C, Lau C . Serum exosomes mediate delivery of arginase 1 as a novel mechanism for endothelial dysfunction in diabetes. Proc Natl Acad Sci U S A. 2018; 115(29):E6927-E6936. PMC: 6055191. DOI: 10.1073/pnas.1721521115. View

17.

Gidlof O, Evander M, Rezeli M, Marko-Varga G, Laurell T, Erlinge D . Proteomic profiling of extracellular vesicles reveals additional diagnostic biomarkers for myocardial infarction compared to plasma alone. Sci Rep. 2019; 9(1):8991. PMC: 6586849. DOI: 10.1038/s41598-019-45473-9. View

18.

Lindsberg P, Carpen O, Paetau A, Karjalainen-Lindsberg M, Kaste M . Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation. 1996; 94(5):939-45. DOI: 10.1161/01.cir.94.5.939. View

19.

Liu V, Huang P . Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc Res. 2007; 77(1):19-29. PMC: 2731989. DOI: 10.1016/j.cardiores.2007.06.024. View

20.

Sun T, Dong Y, Du W, Shi C, Wang K, Tariq M . The Role of MicroRNAs in Myocardial Infarction: From Molecular Mechanism to Clinical Application. Int J Mol Sci. 2017; 18(4). PMC: 5412330. DOI: 10.3390/ijms18040745. View