Abstract
Atherosclerosis could be induced by multiple factors, including hypertension, hyperlipidemia, and smoking, and its pathogenesis has not been fully elucidated. MicroRNAs have been shown to possess great anti-atherosclerotic potential, but the precise function of miR-92a-3p in atherosclerosis and its potential molecular mechanism have not been well clarified. Flow cytometry assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay were performed to evaluate effects of oxidized low-density lipoprotein (ox-LDL) on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs), respectively. Malondialdehyde and superoxide dismutase levels in cell lysate were assessed with biochemical kits. The expression levels of miR-92a-3p and Sirtuin6 (SIRT6) in HUVECs exposed to ox-LDL were estimated by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the protein levels of SIRT6, c-Jun N-terminal kinase (JNK), phosphorylation JNK (p-JNK), p38 mitogen activated protein kinase (p38 MAPK), and phosphorylation p38 MAPK (p-p38 MAPK) were measured by western blot assays. The relationship between miR-92a-3p and SIRT6 was confirmed by dual-luciferase reporter assay. Ox-LDL induced apoptosis and oxidative stress in HUVECs in concentration- and time-dependent manners. Conversely, miR-92a-3p silencing inhibited apoptosis and SIRT6 expression in HUVECs. The overexpression of miR-92a-3p enhanced apoptosis and phosphorylation levels of JNK and p38 MAPK as well as inhibited proliferation in ox-LDL-induced HUVECs. In addition, SIRT6 was a target of miR-92a-3p. miR-92a-3p negatively regulated SIRT6 expression in ox-LDL-induced HUVECs to activate MAPK signaling pathway in vitro. In summary, miR-92a-3p promoted HUVECs apoptosis and suppressed proliferation in ox-LDL-induced HUVECs by targeting SIRT6 expression and activating MAPK signaling pathway.
Highlights
Atherosclerosis is responsible for stroke and coronary artery diseases worldwide, and is involved in inflammation, lipid metabolism, and oxidative stress [1,2]
We found that the miR-92a-3p level was increased in oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs) (Figure 2A)
We verified that treatment with 50 mg/mL of ox-LDL for 48 h reduced cell viability and induced apoptosis and oxidative stress of HUVECs, which was attenuated by miR-92a-3p inhibitor or overexpression of SIRT6
Summary
Atherosclerosis is responsible for stroke and coronary artery diseases worldwide, and is involved in inflammation, lipid metabolism, and oxidative stress [1,2]. Studies have reported that blood miRNAs could function as biomarkers for coronary artery disease [10]. Niculescu et al [12] identified that circulating miR-486 had a close relationship with some lipid metabolism biomarkers. A previous report showed that highdensity lipoprotein (HDL)-transferred miRNA-223 regulated intercellular adhesion molecule-1 expression to reduce inflammation in primary human coronary aortic endothelial cells [13]. The precise relationship miR-92a-3p improves ox-LDL induced-apoptosis in HUVECs between miRNA and lipid metabolism on coronary artery disease is largely unknown [14]
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