Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients
Abstract
:1. Introduction
2. Results
2.1. Patient Groups and Prevalence of Previous History
2.2. MiRNA Expression in Chronic CAD and Acute MI
2.3. MiR-483-5p Regulation in Chronic CAD and Acute MI
2.4. Cardiovascular Disease-Related Medications and Their Association within the Study Groups
2.5. Predicted Gene Target for miR-483-5p
3. Discussion
4. Materials and Methods
4.1. Patient Recruitment and Sample Collection
4.2. RNA Extraction
4.3. Preparation of Libraries and miRNA Sequencing
4.4. Quantitative Real Time PCR (qPCR)
4.5. Bioinformatics and Statistical Analysis
4.6. Identification of Predicted Gene Targets for miR-483-5p
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADAMTS2 | ADAM metallopeptidase with thrombospondin type-1 motif -2 |
ANOVA | One-way analysis of variance |
CAD | Coronary artery disease |
CRP | C-reactive protein |
DNAAF10 | Dynein axonemal assembly factor 10 |
dsDNA | Double-stranded Deoxyribonucleic Acid |
GFR | Glomerular Filtration Rate |
GRK2 | G protein-coupled receptor kinase 2 |
HGSNAT | Heparan-alpha-glucosaminide N-acetyltransferase |
IGF2 | Insulin-like growth factor-2 |
IL-6 | Interleukin 6 |
IL-10 | Interleukin 10 |
IQSEC2 | IQ motif and Sec7 domain ArfGEF 2 |
MDRD | Modification of diet in renal disease |
MI | Myocardial infraction |
MiRDB | An online database for prediction of functional miRNA targets |
MiRNAs | Micro RiboNucleic Acids |
MMP-9 | Matrix metallopeptidase-9 |
MYOM2 | Myomesin 2 |
NCBI | National center for biotechnology information |
NGS | Next generation sequencing |
NSTEMI | Non ST-segment elevation myocardial infraction |
NUDT8 | Nudix hydrolase 8 |
PCI | Percutaneous coronary intervention |
PLA2G5 | Phospholipase A2 group V |
qPCR | Quantitative polymerase chain reaction |
ROC | Receiver operator curve analysis |
RPKM | Reads Per Kilobase of transcript, per Million mapped reads |
SMG6 | SMG6 Nonsense mediated mRNA decay factor |
sPLA2 | Secretory phospholipase A2 |
sPLA2-IIA | Secretory phospholipase A2-IIA |
SRF | Serum response factor |
STEMI | ST-segment elevation myocardial infraction |
TIMP2 | TIMP metallopeptidase inhibitor 2 |
TMM | Trimmed Mean of M |
TNF-α | Tumor necrosis factor alpha |
TRIM7 | Tripartite motif containing 7 |
WBC | White blood cells |
ZMYM6 | Zinc finger MYM-type containing 6 |
ZNF417 | Zinc finger protein 417 |
ZNF584 | Zinc finger protein 584 |
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No CAD n = 23 | CAD (PCI) n = 28 | STEMI n = 22 | NSTEMI n = 26 | ANOVA p Value | |
---|---|---|---|---|---|
Age | 62 ± 10 | 63 ± 9 | 60 ± 8 | 62 ± 9 | 0.632 |
Hypertension | 14 (61%) | 21 (78%) | 11 (50%) | 18 (69%) | 0.188 |
Diabetes mellitus | 10 (43%) | 15 (56%) | 9 (41%) | 8 (31%) | 0.280 |
Hyperlipidemia | 16 (70%) | 17 (63%) | 12 (54%) | 17 (65%) | 0.767 |
Family History of CAD | 8 (35%) | 3 (11%) | 6 (27%) | 9 (35%) | 0.154 |
Smoking | 4 (17%) † | 11 (41%) | 16 (72%) *,‡ | 9 (36%)† | 0.002 |
Renal failure | 0 (0%) | 0 (0%) | 0 (0%) | 2 (8%) | 0.127 |
Previous MI | 0 (0%) | 4 (16) | 0 (0%) | 6 (24%) | 0.011 |
Previous PCI | 0 (0%) **,‡ | 19 (70%) *,†,‡ | 2 (9%) ** | 9 (35%) *,** | <0.0001 |
Atrial fibrillation | 2 (9%) | 0 (0%) | 1 (5%) | 1 (4%) | 0.489 |
Hemoglobin (gr/dL) | 14 ± 2 | 14 ± 2 | 15 ± 1 | 14 ± 2 | 0.328 |
WBC (×1000/dL) | 8.8 ± 2.7 | 9.3 ± 2.1 | 10.8 ± 2.8 | 8.9 ± 3.4 | 0.101 |
Creatinine (mg/dL) | 0.86 ± 0.19 | 0.98 ± 0.32 | 0.98 ± 0.23 | 1.01 ± 0.27 | 0.318 |
GFR (MDRD, ml/min) | 95 ± 25 | 85 ± 24 | 84 ± 22 | 81 ± 21 | 0.251 |
All Patients n = 99 | Odds Ratio | Confidence Interval | Odds Ratio | Confidence Interval | p Value |
---|---|---|---|---|---|
Univariable | Multivariable, stepwise | ||||
Age | 1.001 | 0.94 to 1.07 | |||
Smoking | 12.20 | 2.47 to 60.03 | 4.36 | 1.32 to 14.37 | 0.0155 |
Coronary miRNA483 | 1.01 | 0.783 to 1.30 | |||
Peripheral miRNA483 | 0.77 | 0.59 to 0.98 | 0.83 | 0.69 to 0.99 | 0.0402 |
Patients without previous PCI, n = 68 | |||||
Univariable | Multivariable, stepwise | ||||
Age | 1.04 | 0.97 to 1.12 | |||
Smoking | 11.80 | 2.52 to 55.40 | 6.67 | 1.79 to 24.81 | 0.0046 |
Coronary miRNA483 | 0.98 | 0.76 to 1.25 | |||
Peripheral miRNA483 | 0.73 | 0.55 to 0.96 | 0.78 | 0.61 to 0.99 | 0.0465 |
No CAD n = 23 | CAD (PCI) n = 28 | STEMI n = 22 | NSTEMI n = 26 | ANOVA p Value | |
---|---|---|---|---|---|
Beta blockers | 6 (26%) ** | 16 (57%) *,† | 2 (9%) ** | 5 (19%) | 0.006 |
Angiotensin receptor blockers (ARBs) | 1 (4%) | 1 (4%) | 0 (0%) | 0 (0%) | 0.722 |
Calcium channel blockers (CCBs) | 2 (9%) | 4 (14%) | 2 (9%) | 5 (19%) | 0.340 |
Angiotensin-converting enzyme (ACE) inhibitors | 10 (43%) | 14 (50%) ‡ | 6 (li%) | 2 (8%) ** | 0.044 |
Anticoagulants | 2 (9%) | 1 (4%) | 1 (9%) | 0 (0%) | 0.616 |
Aspirin | 15 (65%) † | 22 (79%) †, ‡ | 4 (18%) *, ** | 7 (26%) ** | <0.001 |
Statins | 14 (61%) | 16 (57%) | 6 (27%) | 9 (35%) | 0.355 |
Gene | Gene Name | Function | Expression |
---|---|---|---|
PLA2G5 | phospholipase A2 group V | Encoded enzyme catalyzes the hydrolysis of membrane phospholipids to generate lysophospholipids and free fatty acids including arachidonic acid. It preferentially hydrolyzes linoleoyl-containing phosphatidylcholine substrates. Secretion of this enzyme is thought to induce inflammatory responses in neighboring cells. | Biased expression in heart (RPKM 14.5), |
NUDT8 | nudix hydrolase 8 | Encoded enzyme predicted to enable magnesium ion binding activity. Predicted to be involved in purine nucleoside bisphosphate catabolic process. Predicted to be located in mitochondria. | Broad expression in heart (RPKM 4.8) |
MYOM2 | myomesin 2 | The giant protein titin, together with its associated proteins, interconnects the major structure of sarcomeres, the M bands and Z discs. The C-terminal end of the titin string extends into the M line, where it binds tightly to M-band constituents of apparent molecular masses of 190 kD and 165 kD. The predicted MYOM2 protein contains 1465 amino acids. Like MYOM1, MYOM2 has a unique N-terminal domain followed by 12 repeat domains with strong homology to either fibronectin type III or immunoglobulin C2 domains. Protein sequence comparisons suggested that the MYOM2 protein and bovine M protein are identical. | Biased expression in heart (RPKM 193.6) |
GRK2 | G protein-coupled receptor kinase 2 | This gene encodes a member of the G protein-coupled receptor kinase family of proteins. The encoded protein phosphorylates the beta-adrenergic receptor as well as a wide range of other substrates including non-GPCR cell surface receptors, and cytoskeletal, mitochondrial and transcription factor proteins. Data from rodent models support a role for this gene in embryonic development, heart function and metabolism. Elevated expression of this gene observed in human patients with heart failure and Alzheimer’s disease. | Broad expression in bone marrow (RPKM 91.8), and other tissues including the heart average expression (10.2 RPKM) |
TIMP2 | TIMP metallopeptidase inhibitor 2 | This gene is a member of the TIMP gene family, a family of natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix. | Ubiquitous expression in many tissues including the heart (68.2 RPKM) |
DNAAF10 | dynein axonemal assembly factor 10 | This gene encodes a protein with two WD40 repeat domains thought to be involved in apoptosis via activation of caspase-3. Multiple transcript variants encoding different isoforms have been found for this gene. | Ubiquitous expression in many tissues including the heart average tissue expression (2.3 RPKM) |
TRIM7 | tripartite motif containing 7 | The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1, a B-box type 2 and a coiled-coil region. The protein localizes to both the nucleus and the cytoplasm, and may represent a participant in the initiation of glycogen synthesis. | Biased expression in 10 tissues including the heart (0.43 RPKM) |
ZNF584 | zinc finger protein 584 | Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. | Biased expression in many tissues amongst them higher expression in the heart (1.4 RPKM) |
ADAMTS2 | ADAM metallopeptidase with thrombospondin type-1 motif -2 | This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. | Broad expression in many tissues including the heart average tissue expression (2.1 RPKM) |
HGSNAT | heparan-alpha-glucosaminide N-acetyltransferase | This gene encodes a lysosomal acetyltransferase, which is one of several enzymes involved in the lysosomal degradation of heparin sulfate. Mutations in this gene are associated with Sanfilippo syndrome C, one type of the lysosomal storage disease mucopolysaccaridosis III, which results from impaired degradation of heparan sulfate. | Ubiquitous expression in many tissues including the heart low-average tissue expression (5.9 RPKM) |
ZNF417 | zinc finger protein 417 | Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. | Ubiquitous expression in many tissues including the heart low-average tissue expression (1.4 RPKM) |
IQSEC2 | IQ motif and Sec7 domain ArfGEF 2 | This gene encodes a guanine nucleotide exchange factor for the ARF family of small GTP-binding proteins. The encoded protein is a component of the postsynaptic density at excitatory synapses, and may play a critical role in cytoskeletal and synaptic organization through the activation of selected ARF substrates including ARF1 and ARF6. Mutations in this gene have been implicated in nonsyndromic X-linked cognitive disability. | Ubiquitous expression in many tissues including the heart low-average tissue expression (0.4 RPKM) |
SMG6 | SMG6 nonsense mediated mRNA decay factor | This gene encodes a component of the telomerase ribonucleoprotein complex responsible for the replication and maintenance of chromosome ends. The encoded protein also plays a role in the nonsense-mediated mRNA decay (NMD) pathway, providing the endonuclease activity near the premature translation termination codon that is needed to initiate NMD. | Ubiquitous expression in many tissues including the heart average tissue expression (2.2 RPKM) |
ZMYM6 | zinc finger MYM-type containing 6 | Predicted to enable DNA binding activity. Involved in cytoskeleton organization and regulation of cell morphogenesis. Predicted to be located in nucleus. | Ubiquitous expression in many tissues including the heart average tissue expression (2.7 RPKM) |
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Volodko, O.; Volinsky, N.; Yarkoni, M.; Margalit, N.; Kusniec, F.; Sudarsky, D.; Elbaz-Greener, G.; Carasso, S.; Amir, O. Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients. Int. J. Mol. Sci. 2023, 24, 8551. https://doi.org/10.3390/ijms24108551
Volodko O, Volinsky N, Yarkoni M, Margalit N, Kusniec F, Sudarsky D, Elbaz-Greener G, Carasso S, Amir O. Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients. International Journal of Molecular Sciences. 2023; 24(10):8551. https://doi.org/10.3390/ijms24108551
Chicago/Turabian StyleVolodko, Olga, Natalia Volinsky, Merav Yarkoni, Nufar Margalit, Fabio Kusniec, Doron Sudarsky, Gabby Elbaz-Greener, Shemy Carasso, and Offer Amir. 2023. "Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients" International Journal of Molecular Sciences 24, no. 10: 8551. https://doi.org/10.3390/ijms24108551
APA StyleVolodko, O., Volinsky, N., Yarkoni, M., Margalit, N., Kusniec, F., Sudarsky, D., Elbaz-Greener, G., Carasso, S., & Amir, O. (2023). Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients. International Journal of Molecular Sciences, 24(10), 8551. https://doi.org/10.3390/ijms24108551