mircroRNA-152 prevents the malignant progression of atherosclerosis via down-regulation of KLF5. Wang Wei,Zhang Ye,Wang Ling,Li Jin,Li Yongxi,Yang Xiaoyan,Wu Yanqing Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Macrophages' function play a vital role in the progression of atherosclerosis (AS), and miRNAs can modulate inflammatory cytokine secretion, lipid uptake and apoptosis of macrophages. miR-152 is down-regulated in the serum samples of AS patients and inhibits the migration of human umbilical vein endothelial cell, suggesting that miR-152 exerts a role in the atherogenesis. Nevertheless, the function of miR-152 in the inflammatory reaction of macrophages remains unexplored. Besides, bioinformatics shows that KLF5 is a direct target of miR-152. As a result, the objective of this study is to investigate the effects and mechanism of miR-152/KLF5 in the inflammatory reaction of macrophages. ApoE knockdown mouse (ApoE) fed with high fat diet (HFD) was used as animal AS models. Ox-LDL treated RAW264.7 cell was used as cell model. Results showed that miR-152 expression was reduced, while KLF5 expression was elevated in the aortic tissues of AS mice, as compared with that of the control mice. Up-regulation of miR-152 significantly reduced the elevated expression of IL-1, IL-6 and TNF-α mediated by ox-LDL in the cultural supernatant of RAW264.7 cells and reduced β-catenin expression, whereas these effects were all neutralized when KLF5 was up-regulated in the base of miR-152 up-regulation. In conclusion, this study illustrates that miR-152 alleviates the pathogenesis of AS through inhibiting inflammatory responses by targeting KLF5, in which β-catenin might involves in. Our study provides a possibility of consideration of miR-152/KLF5 as a target for AS treatment. 10.1016/j.biopha.2018.08.014

Reciprocal Regulation Between miR-148a/152 and DNA Methyltransferase 1 Is Associated with Hyperhomocysteinemia-Accelerated Atherosclerosis. Yang Anning,Sun Yue,Gao Yuan,Yang Songhao,Mao Caiyan,Ding Ning,Deng Mei,Wang Yanhua,Yang Xiaoling,Jia Yuexia,Zhang Huiping,Jiang Yideng DNA and cell biology DNA methyltransferase 1 (DNMT1) and miRNAs are both important regulators of gene expression that have been implicated in the pathogenesis of atherosclerosis. This study was designed to elucidate the potential interaction between DNMT1 and miRNAs in the context of hyperhomocysteinemia (HHcy)-related atherosclerosis. In the aorta of ApoE mice fed a high methionine diet, increased expression of miR-148a/152, with decreased DNMT1 mRNA and protein levels, was detected. Similar changes were observed in cultured foam cells stimulated with homocysteine. When miR-148a/152 was overexpressed using viral vectors, DNMT1 expression was suppressed, whereas the expression of adipose differentiation-related protein (ADRP) was enhanced, and the contents of total cholesterol (TC) and cholesteryl ester (CE) were increased in cultured foam cells. Conversely, downregulation of miR-148a/152 led to elevated DNMT1 expression, reduced ADRP expression, and lowered contents of TC and CE. The luciferase reporter assay verified that DNMT1 is a target gene for miR-148a/152 and overexpression of DNMT1 can partially reverse the miR-148a/152-induced lipid accumulation in foam cells. Meanwhile, we observed that DNMT1 overexpression enhanced DNA methylation and reduced miR-148a/152 expression. Our data showed reciprocal regulation between miR-148a/152 and DNMT1 in foam cells, which likely plays a critical role in HHcy-related atherosclerosis. 10.1089/dna.2017.3651

Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype. European heart journal AIMS:Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. METHODS AND RESULTS:Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. CONCLUSIONS:ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy. 10.1093/eurheartj/ehaa352

Atherosclerosis. Libby Peter,Buring Julie E,Badimon Lina,Hansson Göran K,Deanfield John,Bittencourt Márcio Sommer,Tokgözoğlu Lale,Lewis Eldrin F Nature reviews. Disease primers Atherosclerosis, the formation of fibrofatty lesions in the artery wall, causes much morbidity and mortality worldwide, including most myocardial infarctions and many strokes, as well as disabling peripheral artery disease. Development of atherosclerotic lesions probably requires low-density lipoprotein, a particle that carries cholesterol through the blood. Other risk factors for atherosclerosis and its thrombotic complications include hypertension, cigarette smoking and diabetes mellitus. Increasing evidence also points to a role of the immune system, as emerging risk factors include inflammation and clonal haematopoiesis. Studies of the cell and molecular biology of atherogenesis have provided considerable insight into the mechanisms that link all these risk factors to atheroma development and the clinical manifestations of this disease. An array of diagnostic techniques, both invasive (such as selective coronary arteriography) and noninvasive (such as blood biomarkers, stress testing, CT and nuclear scanning), permit assessment of cardiovascular disease risk and targeting of therapies. An expanding armamentarium of therapies that can modify risk factors and confer clinical benefit is available; however, we face considerable challenge in providing equitable access to these treatments and in maximizing adherence. Yet, the clinical application of the fruits of research has advanced preventive strategies, enhanced clinical outcomes in affected individuals, and improved their quality of life. Rapidly accelerating knowledge and continued research promise to provide further progress in combating this common chronic disease. 10.1038/s41572-019-0106-z