ABSTRACT
AIM: Long non-coding RNAs (lncRNAs) are known to participate in various human diseases, while the role of X inactive-specific transcript (XIST) binding microRNA-340-5p (miR-340-5p) remains seldom studied. We aim to identify the role of the XIST/miR-340-5p/cyclin D1 (CCND1) axis in the myocardial ischaemia-reperfusion injury (MIRI). METHODS AND RESULTS: The mouse MIRI models were established. The expression of XIST, miR-340-5p, and CCND1 in mouse myocardial tissues in MIRI mice was assessed. The MIRI mice were respectively treated with altered XIST, miR-340-5p, or CCND1. The changes of myocardial enzyme activity were assessed, and the cardiac function was evaluated. Myocardial pathological changes, cardiomyocyte apoptosis and related apoptotic factors, oxidative stress and inflammatory factors were observed in myocardial tissues in mice with MIRI. The binding relationships between XIST and miR-340-5p, and between miR-340-5p and CCND1 were confirmed. XIST and CCND1 were up-regulated while miR-340-5p was down-regulated in MIRI mice. Silenced XIST could elevated miR-340-5p expression and reduced CCND1 expression, so as to promoted cardiac function and suppressed myocardial enzyme activity, ameliorated pathological changes, decelerated cardiomyocyte apoptosis by elevating Bcl-2 but reducing the levels of Bax and Caspase-3, attenuated inflammatory response by repressing IL-6 and TNF-α levels, and mitigated oxidative stress by reducing MDA contents and increasing CAT, GSH-Px, and SOD levels in MIRI mice. XIST sponged miR-340-5p and miR-340-5p targeted CCND1. CONCLUSIONS: Knockdown of XIST up-regulates miR-340-5p to relieve MIRI via inhibiting CCND1.
Subject(s)
MicroRNAs , Myocardial Reperfusion Injury , RNA, Long Noncoding/metabolism , Animals , Cyclin D1/genetics , Cyclin D1/metabolism , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardium/pathology , RNA, Long Noncoding/geneticsABSTRACT
BACKGROUND: CD100 is an immune semaphorin family member that highly expressed on T cells, which take part in the development of acute myocardial infarction (AMI). Matrix metalloproteinases (MMPs) are important mediators for membrane-bound CD100 (mCD100) shedding from T cells to generate soluble CD100 (sCD100), which has immunoregulatory effect on T cells. The aim of this study was to investigate modulatory role of CD100 on CD8+ T cell activity in AMI patients. METHODS: Peripheral sCD100 and MMP-2 level, as well as mCD100 level on T cells was assessed in patients with stable angina pectoris (SAP), unstable angina pectoris (UAP), and AMI. The regulatory function of MMP-2 on mCD100 shedding, sCD100 formation, and cytotoxicity of CD8+ T cells was analyzed in direct and indirect contact co-culture system. RESULTS: AMI patients had higher peripheral sCD100 and lower mCD100 expression on CD8+ T cells in comparison with SAP, UAP, and controls. CD8+ T cells in AMI patients showed elevated direct cytotoxicity, enhanced cytokine production, and increased perforin/granzyme B secretion. Recombinant sCD100 stimulation promoted cytolytic function of CD8+ T cells in controls and AMI patients. Furthermore, AMI patients also had elevated circulating MMP-2 level. Recombinant MMP-2 stimulation induced mCD100 shedding from CD8+ T cells and sCD100 generation, resulting in enhancement of CD8+ T cell cytotoxicity in AMI patients. CONCLUSION: Up-regulation of MMP-2 might contribute to elevation of mCD100 shedding and sCD100 formation, leading to increased cytotoxicity CD8+ T cells in AMI patients.
Subject(s)
Antigens, CD/immunology , CD8-Positive T-Lymphocytes/immunology , Myocardial Infarction/immunology , Semaphorins/immunology , Aged , Antigens, CD/metabolism , CD8-Positive T-Lymphocytes/metabolism , Female , Humans , Lymphocyte Activation/immunology , Male , Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 2/immunology , Middle Aged , Myocardial Infarction/metabolism , Protein Isoforms/immunology , Protein Isoforms/metabolism , Semaphorins/metabolismABSTRACT
BACKGROUND: High mobility group box 1 (HMGB1) protein has been identified as a novel pro-inflammatory cytokine in coronary artery disease (CAD). We investigated the relationship between serum HMGB1 level and the severity of coronary artery stenosis. METHODS: Serum HMGB1 concentration in patients was measured by ELISA. All patients underwent coronary angiography and were assigned into groups according to the quartile of HMGB1 level. RESULTS: HMGB1 level in USAP group was higher than that in control and SAP group. HMGB1 level in SAP group was higher than that in control group (p<0.05). Gensini scores in the highest quartile group (group IV), group III and group II were all significantly higher than that in the lowest quartile group (group I). There was significant correlation between angiographic Gensini score and serum level of HMGB1 (r=0.710, p<0.05). However, in subgroup analysis, we found that serum HMGB1 level was only correlated with angiographic Gensini score in SAP patients (r=0.786, p<0.05), but not USAP patients. CONCLUSIONS: Serum HMGB1 level was markedly increased with the severity of coronary artery stenosis in patients with SAP and USAP, especially in SAP patients, which suggested that increased serum HMGB1 may involve in the pathogenesis of atherosclerotic CAD.
