Inhibition of miR-143-3p alleviates myocardial ischemia reperfusion injury via limiting mitochondria-mediated apoptosis.

MicroRNA (miR)-143-3p is a potential regulatory molecule in myocardial ischemia/reperfusion injury (MI/RI), wherein its expression and pathological effects remains controversial. Thus, a mouse MI/RI and cell hypoxia/reoxygenation (H/R) models were built for clarifying the miR-143-3p's role in MI/RI. Following myocardial ischemia for 30 min, mice underwent reperfusion for 3, 6, 12 and 24 h. It was found miR-143-3p increased in the ischemic heart tissue over time after reperfusion. Cardiomyocytes transfected with miR-143-3p were more susceptible to apoptosis. Mechanistically, miR-143-3p targeted B cell lymphoma 2 (bcl-2). And miR-143-3p inhibition reduced cardiomyocytes apoptosis upon H/R, whereas it was reversed by a specific bcl-2 inhibitor ABT-737. Of note, miR-143-3p inhibition upregulated bcl-2 with better mitochondrial membrane potential (Δψm), reduced cytoplasmic cytochrome c (cyto-c) and caspase proteins, and minimized infarction area in mice upon I/R. Collectively, inhibition of miR-143-3p might alleviate MI/RI via targeting bcl-2 to limit mitochondria-mediated apoptosis. To our knowledge, this study further clarifies the miR-143-3p's pathological role in the early stages of MI/RI, and inhibiting miR-143-3p could be an effective treatment for ischemic myocardial disease.

Crosstalk between Circulatory Microenvironment and Vascular Endothelial Cells in Acute Myocardial Infarction.

BACKGROUND: The reason of high mortality of acute myocardial infarction (AMI) was the lack of exploring the cellular and molecular mechanism of AMI. Therefore, we explored the crosstalk among cells, as well as its potential molecular mechanism of mediating AMI. METHODS: The gene expression profile of peripheral blood, endothelial, platelets and mononuclear cells were applied to differentially expressed genes (DEGs) analysis. ClusterProfiler and the package of gene set enrichment analysis (GSEA) were applied to explore the potential functional pathways of DEGs in 3 types of intravascular cells (endothelial, platelets and mononuclear cells) and peripheral blood. Subsequently, we extracted the surface receptors, secreted proteins and extracellular matrix from the up-regulated DEGs to explore their potential interactions mechanism of AMI by crosstalk and pivot analysis. FINDINGS: A total 11 common regulated DEGs (CDEGs) were identified, which might be potential biomarkers for AMI diagnosis. The abnormal pathways involved in DEGs of 3 types of intravascular cells and peripheral blood were shown, which also verified by GSEA. Afterwards, it was found that there was crosstalk in 3 types of intravascular cells and peripheral blood. Furthermore, we constructed a cell-cell interaction map among cells in AMI regulated by exosome lncRNA, which was involved in the development of AMI. Finally, we identified 8 hub genes, which might be potential biomarkers of AMI. INTERPRETATION: The result of this study can not only be used as a reference for subsequent experiments and further exploration, but also contribute to the development of novel cell and molecular therapies.

Loss of exosomal LncRNA HCG15 prevents acute myocardial ischemic injury through the NF-κB/p65 and p38 pathways.

Exosomes are nanosized bilayer membrane vesicles that may mediate intercellular communication by transporting bioactive molecules, including noncoding RNAs, mRNAs, and proteins. Research has shown that exosomes play an important role in acute myocardial infarction (AMI), but the function and regulation of exosomal long noncoding RNAs (lncRNAs) in AMI are unclear. Thus, RNA sequencing (RNA-Seq) was conducted to investigate the exosomal lncRNA transcriptome from MI patients and identified 65 differentially expressed lncRNAs between the MI and control groups. HCG15, one of the differentially expressed lncRNAs, was verified to have the highest correlation with cTnT by qRT-PCR, and it also contributed to the diagnosis of AMI by receiver operating characteristic (ROC) analysis. Upregulation of HCG15 expression facilitated cardiomyocyte apoptosis and inflammatory cytokine production and inhibited cell proliferation. We also confirmed that HCG15 was mainly wrapped in exosomes from AC16 cardiomyocytes under hypoxia, which contributed to cardiomyocyte apoptosis, the release of inflammatory factors, and inhibition of cell proliferation via the activation of the NF-κB/p65 and p38 pathways, whereas suppressing the expression of HCG15exerted opposite effects, In addition, Overexpression of HCG15 aggravated cardiac IR injury in C57BL/6J mice. This study not only helps elucidate exosomal lncRNA function in AMI pathogenesis but also contributes to the development of novel therapeutic strategies.

Transfer of exosomal microRNA-203-3p from dendritic cells to bone marrow-derived macrophages reduces development of atherosclerosis by downregulating Ctss in mice.

Dendritic cell-derived exosomes have been proven to be efficient adjuvant options for anti-tumor vaccines in cancer immunotherapy. However, their potency in atherosclerosis remains unclear. Here we summarize the association of microRNA-203-3p (miR-203-3p) with dendritic cell-derived exosomes and atherosclerosis. Firstly, dendritic cell-derived exosomes and bone marrow-derived macrophages were isolated, after which expression of miR-203-3p and cathepsin S was determined. After the establishment of atherosclerosis mouse models, gain- and loss-of-function experiments were conducted for the analysis of effects of miR-203-3p and cathepsin S on foam-cell formation, lipid accumulation, collagen deposition and serum total cholesterol. The results found high expression of cathepsin S in atherosclerosis mice and downregulation of miR-203-3p in the serum of atherosclerosis patients and ox-LDL-simulated bone marrow-derived macrophages. Cathepsin S was the target gene of miR-203-3p. miR-203-3p transporting from exosomes to bone marrow-derived macrophages resulted in inhibition of cathepsin S expression and atherosclerosis-related phenotypes in bone marrow-derived macrophages, thus alleviating atherosclerosis in mice, and this process was found to involve the p38/MAPK signaling pathway. These findings provided evidence that the transfer of miR-203-3p by dendritic cell-derived exosomes targeted cathepsin S in bone marrow-derived macrophages to attenuate atherosclerosis progression in mice, serving as a promising clinical target for atherosclerosis.

Inhibition of miR­155­5p attenuates the valvular damage induced by rheumatic heart disease.

Autoimmunity is involved in the valvular damage caused by rheumatic heart disease (RHD). Increased evidence has linked microRNAs (miRNAs/miRs) to autoimmune disease. Signal transducer and activator of transcription 3 (STAT3) and sphingosine­1­phosphate receptor 1 (S1PR1) and suppressor of cytokine signaling 1 (SOCS1) have been widely studied for their roles in autoimmunity and inflammation. Thus, the current study aims to investigate the role played by miR­155­5p in RHD­induced valvular damage via the S1PR1, SOCS1/STAT3 and interleukin (IL)­6/STAT3 signaling pathways. An RHD rat model was induced by inactivated Group A streptococci and complete Freund's adjuvant. A recombinant adeno­associated virus (AAV­miR155­inhibitor) was used to inhibit the expression of miR­155­5p in the heart. Inflammation and fibrosis were assessed by hematoxylin and eosin staining and Sirius red staining. The expression of miR­155­5p in valvular tissues and serum exosomes was detected by reverse transcription­quantitative PCR. S1PR1, SOCS1, STAT3, phosphorylated STAT3, IL­6 and IL­17 protein expression was detected by western blotting and immunohistochemistry. The relationships between miR­155­5p and S1PR1 and SOCS1 were detected by dual luciferase assays. Cytokine concentrations were measured by ELISA. The expression of miR­155­5p in valve tissues and serum exosomes was increased along with decreased S1PR1 and activated SOCS1/STAT3 signaling in the RHD model. The expression of IL­6 and IL­17 was increased in the valves and the serum. Dual luciferase assays showed that miR­155­5p directly targeted S1PR1 and SOCS1. Inhibition of valvular miR­155­5p through AAV pretreatment increased S1PR1 expression and inhibited activation of the SOCS1/STAT3 signal pathway as a result of attenuated valvular inflammation and fibrosis as well as a decrease in IL­6 and IL­17 in the valves and serum. These results suggest that inhibition of miR­155­5p can reduce RHD­induced valvular damage via the S1PR1, SOCS1/STAT3 and IL­6/STAT3 signaling pathways.

The Relationship Between Homocysteine, Blood Pressure Variability, and Left Ventricular Hypertrophy in Patients with Essential Hypertension: An Observational Study.

INTRODUCTION: This study aimed to investigate the relationship between homocysteine (Hcy) and blood pressure variability (BPV) and the relationship between Hcy and left ventricular hypertrophy (LVH) in 102 patients with essential hypertension. METHODS: The 102 patients were divided into the Hcy < 10 µmol/L group (n = 47) and the Hcy ≥ 10 µmol/L group (n = 55) according to Hcy concentration. The differences between Hcy and BPV and Hcy and LVH were compared between the two groups. Finally, the correlations between Hcy and BPV and between Hcy and LVH were analyzed. RESULTS: The results showed that there were significant differences between Hcy and BPV and between Hcy and LVH in the two groups. Hcy correlated positively with the coefficient of variation in nighttime diastolic blood pressure and night systolic blood pressure standard deviation (nDBPSD), with correlation coefficients of 0.331 and 0.303 (P < 0.001). At the same time, Hcy correlated positively with interventricular septal thickness and left ventricular posterior wall thickness, which were indicators of LVH, with correlation coefficients of 0.350 and 0.352 (P < 0.001). CONCLUSIONS: There was a correlation between Hcy and BPV and between Hcy and LVH. Attention should also be paid to blood Hcy and BPV for patients with essential hypertension.

Duration of Dual Antiplatelet Therapy and Late Stent Thrombosis Following Percutaneous Coronary Intervention with Second-Generation Drug-Eluting Stents: A Simple Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The aim of this simple meta-analysis was to systematically compare the occurrence of late and very late stent thrombosis with a short versus a longer duration of dual anti-platelet therapy (DAPT) use following the implantation of second-generation drug-eluting stents (DES). METHODS: Randomized controlled trials that compared short- and long-term DAPT use following percutaneous coronary intervention (PCI) with DES and that reported late (> 30 days but < 1 year) and very late (> 1 year) stent thromboses were searched from the bibliographic database of life sciences and biomedical information, which is also known as MEDLINE, as well as other searched databases including EMBASE, the Cochrane Central and http://www.ClinicalTrials.com . Statistical analysis was carried out using RevMan software [odds ratios (OR) and 95% confidence intervals (CIs) represented the results]. RESULTS: This simple analysis consisted of five randomized controlled trials with a total of 7142 patients. The current results showed no significant difference in late stent thrombosis associated with a shorter or longer duration of DAPT use (OR 0.98, 95% CI 0.30-3.18; P = 0.97, I2 = 0%). The result for very late stent thrombosis was also not significantly different (OR 0.30, 95% CI 0.03-2.95; P = 0.31). CONCLUSIONS: This simple analysis showed no impact of DAPT duration on the occurrence of late and very late stent thrombosis. Similar late and very late stent thrombosis rates were observed with 6-month versus 12-month duration of DAPT use following PCI with second-generation DES.