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Updated: May 25, 2025
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Treatment with PCSK9 inhibitors influences microRNAs expression and changes of arterial wall properties: a randomized
Andreja Rehberger Likozar1, Tina Levstek2,3, Tina Karun2
1Department of Vascular Diseases, University Medical Centre Ljubljana, Zaloška Cesta 7, 1000, Ljubljana, Slovenia. andreja.rehbergerlikozar@kclj.si.
Background:
MicroRNAs (miRNAs) are involved in the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), one of the regulators of low-density lipoprotein cholesterol (LDL-C) metabolism, and are directly involved in the atherosclerotic process. The aim of this study was to verify whether treatment with PCSK9 inhibitors (PCSK9i) and changes in the expression of miRNAs involved in PCSK9 metabolism are associated with arterial wall properties in stable post-myocardial infarction (MI) patients with insufficiently regulated LDL-C levels and significantly increased Lp(a) levels.
Methods:
Ninety-five patients after MI were enrolled and randomized to a placebo (N = 31) or PCSK9i group (N = 64). The treatment group received subcutaneous alirocumab 150 mg or evolocumab 140 mg, every 2 weeks. Blood for biochemical and epigenetic analysis was taken and ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima-media thickness (c-IMT) and pulse wave velocity (PWV) were performed initially and after 6 months of treatment. The expression of the selected 5 miRNAs (miR-191-5p, miR-224-5p, miR-337-3p, miR-483-5p, and miR-552-3p) was quantified using quantitative polymerase chain reaction.
Results:
A decrease in c-IMT was associated with a decrease in the expression of miR-337-3p (ρ = 0.329; p = 0.010) and miR-483-5p (ρ = 0.324; p = 0.012). We did not detect any associations between miRNA changes and FMD or PWV.
Conclusions:
Our results suggest that changes in the selected miRNAs are associated with changes in the morphological properties of the arterial wall. We have shown that the decrease in miR-483-5p expression present a good indicator of the regression of morphological atherosclerotic change. The trial registration: The study is registered with CinicalTrials under the number NCT04613167, date of registration November 2nd, 2020. Approval for this study was obtained from the National Medical Ethics Committee of the Republic of Slovenia (reference number: KME 0120-357/2018/8).
Insights
PCSK9 inhibitors (PCSK9i) reduced arterial wall thickness in post-MI patients. Decreased miR-483-5p expression correlated with atherosclerotic regression, indicating its potential as a biomarker for treatment efficacy.
Area of Science:
- Cardiovascular Medicine
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) influence proprotein convertase subtilisin-kexin type 9 (PCSK9) synthesis, a key regulator of low-density lipoprotein cholesterol (LDL-C) metabolism.
- miRNAs are implicated in the atherosclerotic process, making them potential targets for cardiovascular disease management.
- Patients post-myocardial infarction (MI) with suboptimal LDL-C and elevated Lp(a) levels represent a high-risk group for further cardiovascular events.
Purpose of the Study:
- To investigate the association between PCSK9 inhibitor (PCSK9i) treatment and arterial wall properties in stable post-MI patients.
- To determine if changes in specific miRNA expression correlate with alterations in arterial wall characteristics.
- To assess the impact of PCSK9i therapy on carotid intima-media thickness (c-IMT), flow-mediated dilation (FMD), and pulse wave velocity (PWV).
Main Methods:
- A randomized controlled trial involving 95 post-MI patients, with 64 receiving PCSK9i (alirocumab or evolocumab) and 31 receiving placebo for 6 months.
- Biochemical and epigenetic analyses were performed, alongside ultrasound measurements of FMD, c-IMT, and PWV at baseline and after 6 months.
- Quantitative polymerase chain reaction was used to measure the expression levels of five selected miRNAs (miR-191-5p, miR-224-5p, miR-337-3p, miR-483-5p, and miR-552-3p).
Main Results:
- A significant decrease in carotid intima-media thickness (c-IMT) was observed.
- Reduced c-IMT was associated with decreased expression of miR-337-3p (ρ=0.329, p=0.010) and miR-483-5p (ρ=0.324, p=0.012).
- No significant associations were found between miRNA expression changes and flow-mediated dilation (FMD) or pulse wave velocity (PWV).
Conclusions:
- Changes in the expression of specific miRNAs are linked to alterations in arterial wall morphology.
- A decrease in miR-483-5p expression serves as a potential indicator for the regression of morphological atherosclerotic changes.
- These findings highlight the role of miRNAs in PCSK9 inhibitor treatment response and atherosclerotic progression.
