Feng Wang

Epigenetics is closely related to cardiovascular diseases. Genome-wide linkage and association analyses and candidate gene approaches illustrate the multigenic complexity of cardiovascular disease. Several epigenetic mechanisms, such as DNA methylation, histone modification, and noncoding RNA, which are of importance for cardiovascular disease development and regression. Targeting epigenetic key enzymes, especially the DNA methyltransferases, histone methyltransferases, histone acetylases, histone deacetylases and their regulated target genes, could represent an attractive new route for the diagnosis and treatment of cardiovascular diseases. Herein, we summarize the knowledge on epigenetic history and essential regulatory mechanisms in cardiovascular diseases. Furthermore, we discuss the preclinical studies and drugs that are targeted these epigenetic key enzymes for cardiovascular diseases therapy. Finally, we conclude the clinical trials that are going to target some of these processes.

OBJECTIVE: The pathogenesis of coronary artery calcification (CAC) in coronary heart disease (CHD) is mediated by exosomes derived from vascular smooth muscle cells (VSMCs). However, little is known about their underlying mechanism. In this study, we aimed to investigate the differentially expressed miRNAs in VSMCs undergoing induced calcification. METHODS: A cellular calcification model was established using the mouse VSMC line MOVAS-1. Calcium deposition was evaluated by Alizarin Red staining. Exosome sizes were determined by Nanoparticle Tracking Analysis (NTA), and exosome morphology was examined by transmission electron microscopy (TEM). The expression of exosome and calcification biomarkers was analyzed by quantitative real-time PCR (qPCR) and western blotting. Differential miRNA profiles were determined by deep sequencing and bioinformatics. Protein levels in VSMCs experiencing interference by a miR-324-3p inhibitor were detected by western blotting. RESULTS: The MOVAS-1 calcification model was confirmed by Alizarin Red staining and expressional alteration of α-SMA, BMP-2, OPN, and MGP. Exosomes from the calcification model showed expression of exosomal biomarkers and regular exosome diameters, which caused significant calcification in MOVAS-1 cells. In total, 987 and 92 miRNAs were significantly upregulated and downregulated in exosomes from the cellular calcification model as compared with those from MOVAS-1 cells, respectively. Target genes of differential miRNAs were involved in various biological processes such as development, metabolism, and cellular component organization and biogenesis as well as multiple signaling pathways such as protein kinase B (AKT) signaling. The most differentially expressed miRNAs were validated by qPCR, which showed that mmu-let-7e-5p was downregulated and mmu-miR-324-3p was upregulated in exosomes from the MOVAS-1 cellular calcification model. The expression of IGF1R was increased, and the expressions of PIK3CA and MAP2K1 were reduced in MOVAS-1 transfected with a miR-324-3p inhibitor. CONCLUSION: microRNA profiles were significantly altered in exosomes from VSMCs undergoing calcification.

Vascular calcification is the abnormal deposition of calcium phosphate complexes in blood vessels, which is regarded as the pathological basis of multiple cardiovascular diseases. The flowing blood exerts a frictional force called shear stress on the vascular wall. Blood vessels have different hydrodynamic properties due to discrepancies in geometric and mechanical properties. The disturbance of the blood flow in the bending area and the branch point of the arterial tree produces a shear stress lower than the physiological magnitude of the laminar shear stress, which can induce the occurrence of vascular calcification. Endothelial cells sense the fluid dynamics of blood and transmit electrical and chemical signals to the full-thickness of blood vessels. Through crosstalk with endothelial cells, smooth muscle cells trigger osteogenic transformation, involved in mediating vascular intima and media calcification. In addition, based on the detection of fluid dynamics parameters, emerging imaging technologies such as 4D Flow MRI and computational fluid dynamics have greatly improved the early diagnosis ability of cardiovascular diseases, showing extremely high clinical application prospects.

Background. Acute myocardial infarction (AMI) is one of the most critical conditions of coronary heart disease with many uncertainties regarding reduction of ischemia/reperfusion injury, medical treatment strategies, and other aspects. The inflammatory immune response has a bidirectional regulatory role in AMI and plays an essential role in myocardial remodeling after AMI. The purpose of our research was tantamount to explore possible mechanisms of AMI and to analyze the relationship with the immune microenvironment. Methods. We firstly analyzed the expression profile of GSE61144 and HADb to identify differentially expressed autophagy-related genes (DEARGs). Then, we performed GO, functional enrichment analysis, and constructed PPI network by Metascape. A lncRNA-miRNA-mRNA ceRNA network was built, and hub genes were extracted by Cytoscape. After that, we used CIBERSORT algorithm to estimate the proportion of immunocytes, followed by correlation analysis to find relationships between hub DEARGs and immunocyte subsets. Finally, we verified those hub genes in another dataset and cellular experiments qPCR. Results. Compared with controls, we identified 44 DEARGs and then filtered the genes of MCODE by constructing PPI network for further analysis. A total of 45 lncRNAs, 24 miRNAs, 19 mRNAs, 162 lncRNA-miRNA pairs, and 37 mRNA-miRNA pairs were used to construct a ceRNA network, and 4 hub DEARGs (BCL2, MAPK1, RAF1, and PRKAR1A) were extracted. We then estimated 5 classes of immunocytes that differed between AMI and controls. According to the results of correlation analysis, these 4 hub DEARGs may play modulatory effects in immune infiltrating cells, notably in CD8+ T cells and neutrophils. Finally, the same results were verified in GSE60993 and qPCR experiments. Conclusion. Our findings suggest that those hub DEARGs (BCL2, MAPK1, RAF1, and PRKAR1A) and immunocytes probably play functions in the progression of AMI, providing potential diagnostic markers and new perspectives for treatment of AMI.