Exosome-Derived Mediators as Potential Biomarkers for Cardiovascular Diseases: A Network Approach
Abstract
:1. Introduction
1.1. Biogenesis, Characteristics, and Functions of Exosomes
1.1.1. Exosomal Biogenesis
1.1.2. Sorting of Cargo into Exosomes
1.1.3. Characterization of Exosomes
1.1.4. Exosomal Functions
1.2. Exosomal Isolation Techniques
1.2.1. Ultracentrifugation-Based Isolation Techniques
1.2.2. Size-Based Isolation Techniques
1.2.3. Precipitation Methods
1.2.4. Immunoaffinity-Based Techniques
1.3. Exosomes in CVDs
2. Material and Methods
2.1. Literature Search
2.2. Bioinformatic Analysis
3. Results
3.1. Literature Search
3.2. Circulating Exosomal miRNAs in Coronary Artery Disease and Heart Failure Patients
3.3. Circulating Exosomal Proteins in Coronary Artery Disease Patients
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Isolation Method | Main Advantages | Main Disadvantages | Ref. |
---|---|---|---|
Sucrose density gradient ultracentrifugation | Easy to perform, requires little technical expertise. | Time-consuming, risk of exosomal rupture and loss, requires a large volume of samples. | [47,48,49] |
Size-based methods
| Fast method with no requirement for special equipment. | Risk of exosomal rupture and loss. | [50,51,52] |
| Preserves exosomal structure with high purity and good reproducibility. | Laborious, possible contamination with lipoproteins. | [50,53] |
Precipitation | Easy to perform, minimal cost with no requirement for special equipment. | Risk of contamination with lipoproteins. | [54,55] |
Immunoaffinity-based methods | Preserves exosomal structure with high purity, requires a small volume of samples with a low experiment time. | Low yield, exosomal tags need to be established. | [52,56] |
Microfluidics-based methods | Preserves exosomal structure and compositions, requires a small volume of samples and reagent consumption at a low cost. | Lack of method validation, standardization and large-scale tests on clinical samples. | [49,52,57] |
Cardiovascular Disease | Isolation Method | Biofluid | Discovery Cohort Size | Exosome Validation Method | Exosomes Characteristics | Biomarker Candidate(s) | Ref. |
---|---|---|---|---|---|---|---|
Coronary artery disease (CAD) | ExoQuick Exosome Precipitation Solution | Plasma | C57BL/6 mice, n = 5 | Electron microscopy Nanoparticle tracking analysis Western Blotting | n. d. | miR-1, miR-208a, miR-133a, miR-499-5p | [70] |
Ultracentrifugation (sucrose) | Serum | Human, n = 5 | Electron microscopy CD9 staining | n. d. | MYBPC3, VIM | [71] | |
n. d. | Plasma | Tandem stenosis group, mice n = 4 | n. d. | n. d. | miR-223, miR-339, miR-21 | [72] | |
Ultracentrifugation | Plasma | Tandem stenosis group, mice n = 4 | Electron microscopy Western blotting | n. d. | miR-223, miR-339, miR-21 | [73] | |
Ultracentrifugation | Plasma | Human, n = 25 | Mass spectrometry for proteome analysis, using nano–liquid chromatography LTQ Orbitrap XL mass spectrometer | n. d. | n. d. | [74] | |
Acute myocardial infarction (AMI) | ExoQuick Exosome Precipitation Solution | Plasma | C57BL/6 mice, n = 5 | Electron microscopy Nanoparticle tracking analysis Western Blotting | n. d. | miR-1, miR-208a, miR-133a, miR-499-5p | [70] |
ExoQuick Exosome Precipitation Solution | Serum | Human, n = 28 | Transmission electron microscopy Flow cytometry Immunoblotting | CD63 expression | miR-30a | [75] | |
Ultracentrifugation | Plasma; Pericardial fluid | Human, n = 12 | Western Blotting | Rab 5B and CD81 expression | n. d. | [76] | |
Ultracentrifugation | Serum | Human, n = 10 | n. d. | n. d. | Apo-J | [77] | |
Coronary artery dilatation due to Kawasaki disease (KD) | ExoQuick Exosome Precipitation Solution | Serum | Human, n = 6 | Transmission electron microscopy Western blotting | CD9, CD81, and flotillin expression | ITIH4, PROS1, C9, AFM, A1BG IGFALS, C4A, HPX, SERPINC 1, Inter-alpha (Globulin) inhibitor H4 (Plasma Kallikrein-sensitive glycoprotein) variant, AGT, DBP, KNG1, SERPINA 3, LRG1, C4B, HP, CLU, PON3, C3, CD5L, SHBG, FGG, APOL1, CFHR1, FGB, TF, ALB, CFI, IGHM, ALB isoform CRA_k, IGKVA-1, MBL2, TTR, IGKC, APOM, SERPINA 1, CLEC3B | [78] |
Acute heart failure (HF) | Exosome isolation kit | Serum | Human, n = 43 | Electron microscopy Nanoparticle tracking analysis Western Blotting | CD63 and Hsp70 expression | miR-92b-5p, miR-192-5p, miR-320a | [79] |
Exosome isolation kit | Serum | Human, n = 28 | Electron microscopy Nanoparticle tracking analysis Western blotting | Size: 40–150 nm (average 80 nm); CD63 and Hsp70 expression | miR-92b-5p, miR-192-5p, miR-320a | [80] | |
HF | ExoQuick Exosome Precipitation Solution | Serum | Human, n = 4 | Western Blotting | CD63 expression | miR-192, miR-194, miR-34a | [81] |
Ultracentrifugation | Pericardial fluid | Human, n = 51 | n. d. | n. d. | miR-210, let-7b-3p, let-7d-3p, miR-1, miR-125a-5p, miR-126-3p, miR-129-5p, miR-132-3p, miR-133a, miR-135a-5p, miR-135b-5p, miR-138-5p, miR-139-5p, miR-140-5p, miR-143-3p, miR-145-5p, miR-146a-3p, miR-146a-5p, miR-17-5p, miR-181a-5p, miR-181b-5p, miR-181c-5p, miR-208a, miR-20a-5p, miR-21-3p, miR-214-3p, miR-23a-3p, miR-23b-3p, miR-25-3p, miR-30a-3p, miR-30c-5p, miR-30e-3p, miR-320a, miR-330-5p, miR-339-3p, miR-346, miR-34c-3p, miR-365a-3p, miR-375, miR-499a-5p, miR-505-3p, miR-532-3p, miR-671-5p, miR-92b-3p, miR-9-3p | [82] | |
Exosome Isolation kit | Plasma | Human, n = 40 | n. d. | n. d. | miR-486, miR-146a | [83] | |
Idiopathic pulmonary arterial hypertension (IPAH) | Ultracentrifugation | Plasma | Human, n = 5 | Nanoparticle tracking analysis BCA Protein assay Immunoblotting | CD31, CD63 and TSG101 expression | n. d. | [84] |
Ultracentrifugation | Plasma | Human, n = n. d. | Nanoparticle tracking analysis Transmission electron microscopy Western blotting | n. d. | miR-let-7c, miR-let-7d, miR-16, miR-18a, miR-19b, miR-20a, miR-20b, miR-27b, miR-30b, miR-30c, miR-125a-5p, miR-145, miR-146b. miR-148a, miR-195, miR-200b, miR-215, miR-218, miR-221, miR-339-3p, miR-365 | [85] | |
Arterial disease/ cardiovascular risk factors | ExoQuick Exosome Precipitation Solution | Plasma | Human, n = 1012 | BCA Protein assay | n. d. | n. d. | [86] |
(i) Hypertension | Exosome isolation kit | Plasma | Spontaneous hypertensive rats (SHRs), n = n. d. | Dynamic light scattering Western blotting | Size: 10–200 nm diameter (those ranging 30–150 nm accounted for 80%); CD63 and Hsp70 expression | rno-miR-148a-3p, rno-miR-122-5p, rno-miR-143-3p, rno-miR-192-5p, rno-let-7i-5p, rno-miR-215, rno-miR-140-3p, rno-miR-99a-5p, rno-miR-6329, rno-miR-378a-3p, rno-miR-486, rno-miR-378a-5p, rno-miR-6328, rno-miR-187-3p, rno-miR-383-5p, rno-miR-206-3p, rno-miR-425-5p, rno-miR-128-3p, rno-miR-181c-3p, rno-let-7d-5p, rno-miR-191a-3p, rno-miR-185-5p, rno-miR-218a-5p, rno-let-7f-5p, rno-miR-148a-5p, rno-miR-322-3p, rno-miR-181d-5p, rno-miR-223-5p, rno-miR-191a-5p, rno-miR-17-5p, rno-miR-3559-5p, rno-let-7a-5p, rno-miR-15b-5p, rno-miR-223-3p, rno-miR-872-5p, rno-miR-3068-3p | [87] |
Ultracentrifugation | Serum | Cardiac hypertrophic Wistar rats, n = 6 | Electron microscopy Western blotting | n. d. | HSP90, HSC70, CD63, CD9, GAPDH, CD68, miR-17-3p, miR-145-5p, miR-221-3p, miR-222-5p | [88] | |
n. d. | Urine | C57BL6J/Ola mice, n = n. d. | Nanoparticle tracking analysis Western blotting | n. d. | NCC | [89] | |
Ultracentrifugation | Urine | Human, n = 11 | n. d. | n. d. | RAIG-2, SDCBP, NKCC2, TSC, ACTB, RAIG-3, ANPEP, GAPDH, MME, EZR, KRT1, ENO1, LDHB, HSPA8, ANXA2 | [90] | |
(ii) Obesity | n. d. | Plasma | Human, n = 23 | n. d. | n. d. | miR-122 | [91] |
(iii) Type 2 diabetes (T2D) | ExoQuick Exosome Precipitation Solution | Serum | Human, n = 33 | n. d. | n. d. | miR-122-5p, let-7a-3p, miR-26b-3p, miR-193b-5p, miR-4532, miR-432-5p, let-7f-1-3p, miR-183-5p, miR-3656, miR-340-3p, miR-6751-3p, miR-1273a, miR-4484, miR-8485, miR-4644, miR-1273g-3p, miR-4271, miR-7847-3p, miR-4461, miR-6885-5p | [92] |
ExoQuick Exosome Precipitation Solution | Plasma | Human, n = 18 | n. d. | n. d. | miR-326, miR-532-5p, miR-186, miR-127-3p, let-7g, let-7d, miR-126, miR-101, miR-18b, miR-21, miR-199a-3p, miR-502-3p, miR-495, miR-132, miR-15b, miR-200c, miR-223-5p, miR-16, miR-543, miR-195, let-7a, miR-26b, miR-374a, miR-26a, let-7f, ADIPOR1, ADIPOR2, APPL1 | [93] | |
(iv) Diabetic nephropathy | ExoQuick Exosome Precipitation Solution | Serum | Human, n = 33 | n. d. | n. d. | miR-122-5p, miR-432-5p, miR-3656, miR-193b-5p, miR-6087, miR-4488, miR-26b-3p, miR-8485, miR-23a-5p, miR-4532, let-7a-3p, miR-6739-5p, miR-1273a, miR-7641, miR-4461, miR-6751-3p, miR-4484, miR-7847-3p, miR-1273g-3p, miR-140-5p | [92] |
(v) Familial hypercholesterolemia (with a CV event) | Filtration | Plasma | Human, n = 42 | Nanoparticle tracking analysis Flow cytometry (CD63 and CD81) | n. d. | miR-130b, miR-133a, miR-142-3p, miR-200c, miR-324-5p, miR-339-3p, miR-425-5p, miR-660, miR-744, miR-122 | [94] |
(vi) Obstructive sleep apnea (OSA) | Exosome isolation kit | Plasma | Human, n = 8 | Electron microscopy Western blotting | n. d. | hsa-miR-16-5p, hsa-miR-4459, hsa-miR-451a, hsa-miR-6510-5p | [95] |
Exosome isolation kit | Plasma | Human, n = n. d. | Electron microscopy Flow cytometry Western blotting | CD63 expression | n. d. | [96] | |
Exosome isolation kit | Plasma | Human, n = 10 | Electron microscopy | n. d. | n. d. | [97] | |
Myocardial ischemia/reperfusion (IR) | ExoQuick Exosome Precipitation Solution | Plasma | Human, n = 4 | Transmission electron microscopy BCA Protein assay Flow cytometry Western blotting | Cup-shaped membrane-bound vesicles;size: ~100 nm diameter; CD63, CD9 and CD81 expression | miR-24, miR-21, miR-214, miR-132, miR-195, miR-210, miR-144, miR-150, miR-34a | [98] |
Ultracentrifugation | Serum | MI Wistar rats, n = 3 | BCA Protein assay Western blotting | CD9 and Hsp90 expression | miR-21, miR-29a, miR-30a, miR-133a | [99] | |
Coronary artery bypass graft (CABG) | Column-based system | Plasma | Human, n = 21 | Nanoparticle tracking analysis Transmission electron microscopy Western blotting | n. d. | miR-1, miR-23a, miR-24, miR-92a, miR-126, miR-133a, miR-133b, miR-208a, miR-208b, miR-210, miR-223, miR-451 | [100] |
miRNA | Cardiovascular Disease | Variation | Included/Not Included in the Vesiclepedia |
---|---|---|---|
miR-133a | Coronary artery disease (CAD) | + | Included |
miR-208a | Coronary artery disease (CAD) | + | Not included |
miR-1 | Coronary artery disease (CAD) | + | Not included |
miR-499-5p | Coronary artery disease (CAD) | + | Not included |
miR-92b-5p | Coronary artery disease (CAD) | + | Not included |
miR-30a | Coronary artery disease (CAD) | + | Not included |
miR-192 | Heart failure (HF) | + | Included |
miR-194 | Heart failure (HF) | + | Included |
miR-146a | Heart failure (HF) | + | Included |
miR-92b-5p | Heart failure (HF) | + | Not included |
Gene Name | Cardiovascular Disease | Variation | Included/Not Included in the Vesiclepedia |
---|---|---|---|
AGT | Coronary artery disease (CAD) | + | Included |
C4B | Coronary artery disease (CAD) | + | Included |
HP | Coronary artery disease (CAD) | + | Included |
FGG | Coronary artery disease (CAD) | + | Included |
FGB | Coronary artery disease (CAD) | + | Included |
VIM | Coronary artery disease (CAD) | + | Not included |
ITIH4 | Coronary artery disease (CAD) | + | Not included |
C9 | Coronary artery disease (CAD) | + | Not included |
IGKC | Coronary artery disease (CAD) | + | Not included |
MYBPC3 | Coronary artery disease (CAD) | + | Not included |
SERPINA3 | Coronary artery disease (CAD) | + | Not included |
LRG1 | Coronary artery disease (CAD) | + | Not included |
CFHR1 | Coronary artery disease (CAD) | + | Not included |
IGKVA-1 | Coronary artery disease (CAD) | + | Not included |
PROS1 | Coronary artery disease (CAD) | − | Included |
C4A | Coronary artery disease (CAD) | − | Included |
A1BG | Coronary artery disease (CAD) | − | Included |
KNG1 | Coronary artery disease (CAD) | − | Included |
CLU | Coronary artery disease (CAD) | − | Included |
C3 | Coronary artery disease (CAD) | − | Included |
CD5L | Coronary artery disease (CAD) | − | Included |
APOL1 | Coronary artery disease (CAD) | − | Included |
TF | Coronary artery disease (CAD) | − | Included |
ALB | Coronary artery disease (CAD) | − | Included |
MBL2 | Coronary artery disease (CAD) | − | Included |
TTR | Coronary artery disease (CAD) | − | Included |
SERPINA1 | Coronary artery disease (CAD) | − | Included |
AFM | Coronary artery disease (CAD) | − | Not included |
IGFALS | Coronary artery disease (CAD) | − | Not included |
HPX | Coronary artery disease (CAD) | − | Not included |
SERPINC1 | Coronary artery disease (CAD) | − | Not included |
DBP | Coronary artery disease (CAD) | − | Not included |
CFI | Coronary artery disease (CAD) | − | Not included |
IGHM | Coronary artery disease (CAD) | − | Not included |
APOM | Coronary artery disease (CAD) | − | Not included |
CLEC3B | Coronary artery disease (CAD) | − | Not included |
PON3 | Coronary artery disease (CAD) | − | Not included |
SHBG | Coronary artery disease (CAD) | − | Not included |
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Moreira-Costa, L.; Barros, A.S.; Lourenço, A.P.; Leite-Moreira, A.F.; Nogueira-Ferreira, R.; Thongboonkerd, V.; Vitorino, R. Exosome-Derived Mediators as Potential Biomarkers for Cardiovascular Diseases: A Network Approach. Proteomes 2021, 9, 8. https://doi.org/10.3390/proteomes9010008
Moreira-Costa L, Barros AS, Lourenço AP, Leite-Moreira AF, Nogueira-Ferreira R, Thongboonkerd V, Vitorino R. Exosome-Derived Mediators as Potential Biomarkers for Cardiovascular Diseases: A Network Approach. Proteomes. 2021; 9(1):8. https://doi.org/10.3390/proteomes9010008
Chicago/Turabian StyleMoreira-Costa, Liliana, António S. Barros, André P. Lourenço, Adelino F. Leite-Moreira, Rita Nogueira-Ferreira, Visith Thongboonkerd, and Rui Vitorino. 2021. "Exosome-Derived Mediators as Potential Biomarkers for Cardiovascular Diseases: A Network Approach" Proteomes 9, no. 1: 8. https://doi.org/10.3390/proteomes9010008