Association between low levels of serum miR-638 and atherosclerotic plaque vulnerability in patients with high-grade carotid stenosis

Abstract

OBJECTIVE Carotid artery atherosclerosis is a major cause of ischemic stroke. However, reliable criteria to identify patients with high-risk carotid plaques beyond the severity of stenosis are still lacking. Circulating microRNAs (miRNAs) are being postulated as biomarkers for a variety of vascular immune-inflammatory diseases. The authors investigated whether cell-free circulating miR-638, highly expressed in vascular smooth muscle cells and implicated in proliferative vascular diseases, is associated with vulnerable atherosclerotic plaques in high-risk patients with advanced carotid artery stenosis undergoing carotid endarterectomy (CEA). METHODS The authors conducted a prospective study in 22 consecutive symptomatic patients with high-grade carotid stenosis undergoing CEA and 36 age- and sex-matched patients without ischemic stroke history or carotid atherosclerosis (control group). In addition, they reviewed data from a historical group of 9 CEA patients who underwent long-term follow-up after revascularization. Total RNA was isolated from all serum samples, and relative miR-638 expression levels were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and compared among groups. A correlation analysis of serum miR-638 levels with vascular risk factors and treatments, and with plaque features, was performed. The ability of serum miR-638 to discriminate between the non-CEA control group and the different CEA groups was assessed by receiver operating characteristic evaluation. A logistic regression model was employed to examine the association between stratified CEA patients and serum miR-638 levels. RESULTS Serum levels of miR-638 were significantly lower in symptomatic CEA patients (p = 0.009) and particularly in the subgroup of CEA patients who had experienced stroke (p = 0.0006) than in non-CEA controls. Discrimination of high-risk plaques was accurate (area under the curve [AUC] 0.66 for symptomatic CEA patients in general and 0.76 for those who had experienced stroke). When only patients with high cardiovascular risk were considered, the diagnostic value of serum miR-638 from symptomatic CEA patients and CEA patients who had experienced stroke improved (AUC 0.79 and 0.85). Moreover, serum miR-638 was negatively correlated with the occurrence of stroke, smoker status, presence of bilateral pathology, coronary artery disease, and cholesterol treatment; and with the high-risk fibroatheroma plaques extracted from CEA patients. Multivariate logistic regression analysis demonstrated that serum miR-638 was an independent predictor of plaque instability. Furthermore, serum miR-638 appeared to attain good discrimination for atherosclerotic stenosis in CEA patients based on analysis of blood samples obtained in the historical group before and 5 years after intervention (p = 0.04) (AUC = 0.79). CONCLUSIONS According to this preliminary proof-of-concept study, serum miR-638 might constitute a promising noninvasive biomarker associated with plaque vulnerability and ischemic stroke, partic...

The c.*52 A/G and c.*773 A/G Genetic Variants in the UTR′3 of the LDLR Gene Are Associated with the Risk of Acute Coronary Syndrome and Lower Plasma HDL-Cholesterol Concentration

“…Alternatively, miR-638 is a regulator of the platelet-derived growth factor-BB (PDGF-BB), which is released primarily by vascular endothelial cells and platelets at the sites of vascular injury. Of note, this miRNA has been identified as one of the most potent stimulants for the VSMC proliferation and migration, through the modulation of several transcription factors and key molecular signaling pathways [ 28 , 29 ]. However, the effects of miR-200a or miR-638 on plasma lipid levels has not been previously reported.…”

Epigenetic Biomarkers in Cardiovascular Diseases

“…Thus, miR-200c could be a biomarker of atherosclerotic plaque progression and clinically useful for identifying patients at high embolic risk (Magenta et al, 2018). Along the same lines, lower serum levels of miR-638 may be a suitable biomarker of plaque vulnerability and ischemic stroke in individuals with high cardiovascular risk (Luque et al, 2018). With the intention to explore the role of miRNAs associated with carotid atherosclerosis, Mao et al (2018) analyzed the genes differentially expressed between primary and advanced atherosclerotic plaques using two public datasets from the Gene Expression Omnibus (GEO) databases.…”

Sensitive to the effects of environmental factors miR-638 and common diseases

“…2). Интересно, что у пациентов с заболеваниями сердечно-сосудистой системы, как и в случае онкологических заболеваний, во-первых, зафиксирован более низкий уровень miR-638, во-вторых, для пациентов с более тяжелой клинической картиной были характерны еще более низкие уровни данной микроРНК [48]. В этом исследовании установлено, что уровень данной микроРНК был ниже у курильщиков по сравнению с некурящими пациентами, что согласуется с данными об увеличении уровня метилирования CpG-сайта данной miR-638 у курильщиков [10].…”

“…Для ряда из перечисленных выше заболеваний miR-638 рассматривают не только как диагностический маркер, но и как терапевтическую мишень. Так, уровень miR-638 в сыворотке крови предлагают использовать как неинвазивный биомаркер уязвимости бляшек и вероятности ишемического инсульта, особенно у лиц с риском сердечно-сосудистых осложнений [48]. Существует мнение, что изменение уровня miR-638 в гладкомышечных клетках сосудов можно быть полезным в лечении пролиферативных заболеваний сосудов [64].…”