Abstract Autophagy plays a critical role in the physiology and pathophysiology of hepatocytes. High levels of homocysteine (Hcy) promote autophagy in hepatocytes, but the underlying mechanism is still unknown. Here, we investigated the relation between Hcy increased autophagy levels and the expression of nuclear transcription factor EB (TFEB). We demonstrate that Hcy increased autophagy levels is mediated by upregulation of TFEB. Silencing TFEB decreases the autophagy-related protein LC3BII/I and increases p62 expression levels in hepatocytes after exposure to Hcy. Moreover, the effect of Hcy on the expression of TFEB is regulated by hypomethylation of TFEB promoter catalyzed by DNA methyltransferase 3b (DNMT3b). In summary, this study shows that Hcy can activate autophagy by inhibiting DNMT3b-mediated DNA methylation and upregulating TFEB expression. These findings provide another new mechanism for Hcy-induced autophagy in hepatocytes.
Cardiovascular disease (CVD) caused by atherosclerosis has become a main threaten for human health. As an independent risk factor, hyperhomocysteinemia (HHcy) played an important role in the pathogenesis of atherosclerosis by regulating DNA methylation modification and autophagy of macrophages. In this study, we constructed a new kind of macro-liposome nanoparticle by hybridizing liposome with macrophages membranes (Møm) to encapsulate hydroxysafflower yellow A (HSYA). Assertion of Hyaluronic acid (HA) on the macro-liposome NPs was adopted to endow nanodrug targeting ability. In vitro results showed that the prepared macro-liposome nanoparticles can significantly inhibit Atg13 DNA methylation, while enhance autophagy of macrophages to promote cholesterol efflux, as well. In vivo studies have shown that the HA modification made the macro-liposome NPs an ideal decoy for targeting plaques. Thus, the macro-liposome NPs with prolonged blood circulation time, and improved targeting ability can achieve optimal HSYA accumulation at the region of atherosclerotic plaques to obtain high efficacy. According to our point, the nano-drug delivery system with high immune escape capability provided a feasible therapeutic strategy for efficient atherosclerosis therapy.
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases, such as atherosclerosis. HHcy promotes atherogenesis by modifying the histone methylation patterns and miRNA regulation. In this study, we investigated the effects of homocysteine (Hcy) on the expression of enhancer of zeste homolog 2 (EZH2), and tested our hypothesis that Hcy-induced atherosclerosis is mediated by increased EZH2 expression, which is regulated by miR-92a. The levels of EZH2 and H3K27me3 were increased in the aorta of ApoE-/- mice fed a high-methionine diet for 16 weeks, whereas miR-92a expression was decreased. Over-expression of EZH2 increased H3K27me3 level and the accumulation of total cholesterol and triglycerides in the foam cells. Furthermore, upregulation of miR-92a reduced EZH2 expression in the foam cells. These data suggested that EZH2 plays a key role in Hcy-mediated lipid metabolism disorders, and that miR-92a may be a novel therapeutic target in Hcy-related atherosclerosis.
The present study aimed to confirm whether the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) is a sensitive indicator, and whether it can be used as a biomarker for the clinical diagnosis of atherosclerosis. Apolipoprotein E (ApoE)-/- mice were randomly divided into four groups and fed with a high methionine diet for 15 weeks. Serum levels of homocysteine (Hcy) were measured using an automatic biochemistry analyzer. The concentrations of SAM and SAH were determined using high‑performance liquid chromatography. The methylation levels of B1 repetitive elements, adipocyte fatty acid binding protein (FABP4), monocyte chemoattractant protein-1 (MCP-1) and extracellular superoxide dismutase (EC‑SOD) were analyzed using nested touchdown-methylation-specific-polymerase chain reaction analysis. After 15 weeks, compared with the normal control group, serum concentrations of Hcy were significantly increased by 1.15‑, 2.54‑ and 1.17‑fold (P<0.05) in the ApoE‑/‑ control group, Meth group and Meth‑F group, respectively. The sizes of the atherosclerotic lesions were increased in the ApoE‑/‑ control group, Meth group and Meth‑F group, by up to 1.44‑, 2.40‑ and 1.45‑fold, respectively, compared with the normal control group (P<0.05). The concentrations of SAM were significantly increased by 3.02‑, 3.42‑ and 2.46‑fold in the ApoE‑/‑ control group, Meth group and Meth‑F group, respectively (P<0.05). The ratios of SAM/SAH were increased by 1.67‑ and 2.75‑fold in the in ApoE‑/‑ control group and Meth group, respectively, compared with the normal control group. The methylation levels of B1 repetitive elements, FABP4, MCP‑1 and EC‑SOD were decreased and exhibited hypomethylation. The methylation statuses of these genes were correlated with the ratio of the serum levels of SAM and SAH. These findings suggested that the SAM/SAH ratio is a biomarker and may provide a sensitive indicator for the clinical diagnosis of atherosclerosis.
It has been demonstrated that homocysteine (Hcy) can cause inflammatory diseases. Long noncoding RNAs (lncRNA) and microRNAs (miRNAs) are involved in this biological process, but the mechanism underlying Hcy-induced inflammation remains poorly understood. Here, we found that lncRNA TGFB3-AS1 was highly expressed in macrophages treated with Hcy and the peripheral blood monocytes from cystathionine beta-synthase heterozygous knockout (CBS+/-) mice with a high-methionine diet using lncRNA microarray. In vivo and in vitro experiments further confirmed that TGFB3-AS1 accelerated Hcy-induced inflammation of macrophages through the Rap1a/wnt signaling pathway. Meanwhile, TGFB3-AS1 interacted with Rap1a and reduced degradation of Rap1a through inhibiting its ubiquitination in macrophages treated with Hcy. Rap1a mediated inflammation induced by Hcy and serves as a direct target of miR-144. Moreover, TGFB3-AS1 regulated miR-144 by binding to pri-miR-144 and inhibiting its maturation, which further regulated Rap1a expression. More importantly, we found that high expression of TGFB3-AS1 was positively correlated with the levels of Hcy and proinflammatory cytokines in serum of healthy individuals and patients with HHcy. Our study revealed a novel mechanism by which TGFB3-AS1 promoted inflammation of macrophages through inhibiting miR-144 maturation to stay miR-144 regulated inhibition of functional Rap1a expression.
Objective The objective of this study was to identify a novel gene and its potential mechanisms associated with susceptibility to gestational diabetes mellitus (GDM) through an integrative approach.
Homocysteine (Hcy) is an independent risk factor for atherosclerosis, but the underlying molecular mechanisms are not known. We investigated the effects of Hcy on fatty acid‐binding protein 4 (FABP4), and tested our hypothesis that Hcy‐induced atherosclerosis is mediated by increased FABP4 expression and decreased methylation. The FABP4 expression and DNA methylation was assessed in the aorta of ApoE −/− mice fed high‐methionine diet for 20 weeks. Over‐expression of FABP4 enhanced accumulation of total cholesterol and cholesterol ester in foam cells. The up‐regulation of DNA methyltransferase 1 (DNMT1) promoted the methylation process and decreased FABP4 expression. These data suggest that FABP4 plays a key role in Hcy‐mediated disturbance of lipid metabolism and that DNMT1 may be a novel therapeutic target in Hcy‐related atherosclerosis.
Ischemic postconditioning (IPostC) is an endogenous protective mechanism to reduce ischemia-reperfusion (I/R) injury. However, whether IPostC protects aged cardiomyocytes against I/R injury is not fully understood. Considering the protective function of microRNA 30a (miR-30a) against ischemia-induced injury in H9C2 cells, its role in the protective effects of IPostC on I/R injury of aged cardiomyocytes was investigated further.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)