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Dysregulation of MicroRNA Regulatory Network in Lower Extremities Arterial Disease.

ABSTRACT: Atherosclerosis and its comorbidities are the major contributors to the global burden of death worldwide. Lower extremities arterial disease (LEAD) is a common manifestation of atherosclerotic disease of arteries of lower extremities. MicroRNAs belong to epigenetic factors that regulate gene expression and have not yet been extensively studied in LEAD. We aimed to indicate the most promising microRNA and gene expression signatures of LEAD, to identify interactions between microRNA and genes and to describe potential effect of modulated gene expression. High-throughput sequencing was employed to examine microRNAome and transcriptome of peripheral blood mononuclear cells of patients with LEAD, in relation to controls. Statistical significance of microRNAs and genes analysis results was evaluated using DESeq2 and uninformative variable elimination by partial least squares methods. Altered expression of 26 microRNAs (hsa-let-7f-1-3p, hsa-miR-34a-5p, -122-5p, -3591-3p, -34a-3p, -1261, -21-5p, -15a-5p, -548d-5p, -34b-5p, -424-3p, -548aa, -548t-3p, -4423-3p, -196a-5p, -330-3p, -766-3p, -30e-3p, -125b-5p, -1301-3p, -3184-5p, -423-3p, -339-3p, -138-5p, -99a-3p, and -6087) and 14 genes (AK5, CD248, CDS2, FAM129A, FBLN2, GGT1, NOG, NRCAM, PDE7A, RP11-545E17.3, SLC12A2, SLC16A10, SLC4A10, and ZSCAN18) were the most significantly differentially expressed in LEAD group compared to controls. Discriminative value of revealed microRNAs and genes were confirmed by receiver operating characteristic analysis. Dysregulations of 26 microRNAs and 14 genes were used to propose novel biomarkers of LEAD. Regulatory interactions between biomarker microRNAs and genes were studied in silico using R multiMiR package. Functional analysis of genes modulated by proposed biomarker microRNAs was performed using DAVID 6.8 tools and revealed terms closely related to atherosclerosis and, interestingly, the processes involving nervous system. The study provides new insight into microRNA-dependent regulatory mechanisms involved in pathology of LEAD. Proposed microRNA and gene biomarkers of LEAD may provide new diagnostic and therapeutic opportunities.

SUBMITTER: Bogucka-Kocka A

PROVIDER: S-EPMC6892359 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Dysregulation of MicroRNA Regulatory Network in Lower Extremities Arterial Disease.

Bogucka-Kocka Anna A Zalewski Daniel P DP Ruszel Karol P KP Stępniewski Andrzej A Gałkowski Dariusz D Bogucki Jacek J Komsta Łukasz Ł Kołodziej Przemysław P Zubilewicz Tomasz T Feldo Marcin M Kocki Janusz J

Frontiers in genetics 20191122

Atherosclerosis and its comorbidities are the major contributors to the global burden of death worldwide. Lower extremities arterial disease (LEAD) is a common manifestation of atherosclerotic disease of arteries of lower extremities. MicroRNAs belong to epigenetic factors that regulate gene expression and have not yet been extensively studied in LEAD. We aimed to indicate the most promising microRNA and gene expression signatures of LEAD, to identify interactions between microRNA and genes and ...[more]

PMID: 31827490

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Project description:ObjectiveTangbi capsule (TBC) is a traditional Chinese medicine prescription, which has the potential to improve the vascular insufficiency of lower extremities and limb numbness in diabetes. However, the potential mechanism remains unknown. This study aims to investigate the pharmacological effects and mechanism of TBC on rats with diabetic lower extremities arterial disease (LEAD).MethodsThe mechanism of TBC on diabetic LEAD was investigated through metabolomics and transcriptomics analysis, and the main components of TBC were determined by mass spectrometry. The efficacy and mechanism of TBC on diabetic LEAD rats were investigated through in vitro experiments, histopathology, blood flow monitoring, western blot, and real-time polymerase chain reaction.ResultsMass spectrometry analysis identified 31 active chemical components in TBC including (2R)-2,3-Dihydroxypropanoic acid, catechin, citric acid, miquelianin, carminic acid, salicylic acid, formononetin, etc. In vitro analysis showed that TBC could reduce endothelial cell apoptosis and promote angiogenesis. Histopathological analysis showed that TBC led to an obvious improvement in diabetic LEAD as it improved fibrous tissue proliferation and reduced arterial wall thickening. In addition, TBC could significantly increase the expression levels of HIF-1α, eNOS, and VEGFA proteins and genes while reducing that of calpain-1 and TGF-β, suggesting that TBC can repair vascular injury. Compared with the model group, there were 47 differentially expressed genes in the whole blood of TBC groups, with 25 genes upregulated and 22 downregulated. Eighty-seven altered metabolites were identified from the serum samples. Combining the changes in differentially expressed genes and metabolites, we found that TBC could regulate arginine biosynthesis, phenylalanine metabolism, pyrimidine metabolism, arachidonic acid metabolism, pyrimidine metabolism, arachidonic acid metabolism, nucleotide metabolism, vitamin B6 metabolism and other metabolic pathways related to angiogenesis, immune-inflammatory response, and cell growth to improve diabetic LEAD.ConclusionTBC improved vascular endothelial injury, apoptosis, lipid accumulation, liver and kidney function, and restored blood flow in the lower extremities of diabetic LEAD rats. The mechanism of TBC in the treatment of diabetic LEAD may be related to the modulation of inflammatory immunity, lipid metabolism, and amino acid metabolism. This study presented preliminary evidence to guide the use of TBC as a therapy option for diabetic LEAD.

Project description:AIM:To assess the frequency of carotid artery disease (CAD) and lower extremities artery disease (LEAD) in patients with chronic obstructive pulmonary disease (COPD) and their relation to the severity of airflow limitation and the level of C-reactive protein (CRP). METHODS:We performed a cross-sectional study including 60 patients with COPD (52 male, 8 female), aged 40 to 80 years, initially diagnosed according to the actual criteria. Also, 30 subjects in whom COPD was excluded, matched to COPD patients by sex, age, body mass index and smoking status, served as controls. All study subjects completed questionnaire and underwent pulmonary evaluation (dyspnea severity assessment, baseline and post-bronchodilator spirometry, gas analyses, and chest X-ray), angiological evaluation by Doppler ultrasonography and measurement of serum CRP level. RESULTS:We found a statistically significant difference between the frequency of carotid plaques in COPD patients as compared to their frequency in controls (65% vs 30%; P = 0.002). The mean value of intima-media thickness (IMT) in COPD patients with CAD was significantly higher than its mean value in controls (0.8 ± 0.2 vs. 0.7 ± 0.2; P = 0.049). IMT value in COPD patients with CAD was significantly related to the degree of airflow limitation, i.e. to the degree of FEV1 decline (P = 0.000), as well as to the serum CRP level (P = 0.001). We found a statistically significant difference between the frequency of COPD patients with LEAD as compared to the frequency of LEAD in controls (78.3% vs 43.3%; P = 0.001). According to the Fontaine classification, COPD patients with LEAD were categorized in the stages I, IIA and IIB (53.3%, 30% and 16.7%, respectively), whereas all controls with LEAD were categorized in the Fontaine stage I. Among COPD patients with LEAD there was significant association between disease severity and clinical manifestations due to the vascular changes (P = 0.001) and serum CRP level (P = 0.001). CONCLUSION:Our findings suggest higher prevalence and higher severity of vascular changes in COPD patients as compared to their prevalence and severity in non-COPD subjects. Prevalence and severity of vascular changes in COPD patients were significantly related to the severity of airflow limitation and serum CRP levels.

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Dysregulation of MicroRNA Regulatory Network in Lower Extremities Arterial Disease.

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Dysregulation of MicroRNA Regulatory Network in Lower Extremities Arterial Disease.

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