TLR4 signaling: a potential therapeutic target in ischemic coronary artery disease.

Atherosclerosis has been widely considered as a chronic inflammation process, which triggers a wide range of cardiovascular diseases such as ischemic coronary artery disease (CAD). Toll-like receptor 4 (TLR4), a primary receptor of the innate immune system, plays a pivotal role in the initiation and progression of atherosclerosis. Here we summarize recent progress on understanding the activation and function of TLR4 signaling in the initiation and development of CAD, with the focus on the role of TLR4 as a link between CAD and other inflammatory diseases. Furthermore, we list a variety of drugs which exert anti-atherosclerosis effects via targeting TLR4 signaling. Finally, we discuss the promise of TLR4 signaling as a therapeutic target for CAD.

Image denoising using nonsubsampled shearlet transform and twin support vector machines.

Denoising of images is one of the most basic tasks of image processing. It is a challenging work to design a edge/texture-preserving image denoising scheme. Nonsubsampled shearlet transform (NSST) is an effective multi-scale and multi-direction analysis method, it not only can exactly compute the shearlet coefficients based on a multiresolution analysis, but also can provide nearly optimal approximation for a piecewise smooth function. Based on NSST, a new edge/texture-preserving image denoising using twin support vector machines (TSVMs) is proposed in this paper. Firstly, the noisy image is decomposed into different subbands of frequency and orientation responses using the NSST. Secondly, the feature vector for a pixel in a noisy image is formed by the spatial geometric regularity in NSST domain, and the TSVMs model is obtained by training. Then the NSST detail coefficients are divided into information-related coefficients and noise-related ones by TSVMs training model. Finally, the detail subbands of NSST coefficients are denoised by using the adaptive threshold. Extensive experimental results demonstrate that our method can obtain better performances in terms of both subjective and objective evaluations than those state-of-the-art denoising techniques. Especially, the proposed method can preserve edges and textures very well while removing noise.

Hypermethylation of DDAH2 promoter contributes to the dysfunction of endothelial progenitor cells in coronary artery disease patients.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) may be a biomarker for vascular function and cardiovascular risk in patients with coronary artery disease (CAD). Dimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the function of EPCs. This study aimed to examine whether hypermethylation of DDAH2 promoter contributes to impaired function of EPCs in CAD patients. METHODS: Peripheral blood mono-nuclear cells from 25 CAD patients and 15 healthy volunteers were collected and differentiated into EPCs. EPCs were tested for their adhesive capability. DDAH2 mRNA expression was analyzed by real-time PCR, and the methylation of DDAH2 promoter was detected by bisulfite genomic sequencing. RESULTS: DDAH2 promoter in EPCs from CAD patients was hypermethylated and the methylation level was negatively correlated to DDAH2 mRNA level and adhesion function of EPCs. Homocysteine impaired the adhesion function of EPCs, accompanied by lower DDAH2 expression and higher methylation level of DDAH2 promoter, compared to controls. These effects of homocysteine were reversed by pretreatment with Aza, an inhibitor of DNA methyltransferase. CONCLUSION: Hypermethylation in DDAH2 promoter is positively correlated to the dysfunction of EPCs in CAD patients. Homocysteine disrupts EPCs function via inducing the hypermethylation of DDAH2 promoter, suggesting a key role of epigenetic mechanism in the progression of atherosclerosis.

Epigallocatechin-3-gallate inhibits homocysteine-induced apoptosis of endothelial cells by demethylation of the DDAH2 gene.

Our previous study showed that hypermethylation of dimethylarginine dimethylaminohydrolase 2 contributes to homocysteine-induced apoptosis of human umbilical vein endothelial cells. Epigallocatechin-3-gallate is a green tea-derived phenol which has been proved beneficial on atherosclerosis. It was demonstrated that epigallocatechin-3-gallate inhibits DNA methyltransferase activity and reactivates methylation-silenced genes in cancer cells. The aim of this study was to address whether epigallocatechin-3-gallate could induce DNA demethylation of the dimethylarginine dimethylaminohydrolase 2 gene, contributing to prevent endothelial cells from apoptosis induced by homocysteine. Human umbilical vein endothelial cells (ATCC, CRL-2480) were treated with homocysteine (1 mM) for 48 hours with or without epigallocatechin-3-gallate (20 µM) or 5-Aza (DNA methyltransferase inhibitor, 5 µM). Apoptosis rate of human umbilical vein endothelial cells was assayed by flow cytometry with an annexin V-FITC apoptosis detection kit. The mRNA and protein expression level of dimethylarginine dimethylaminohydrolase 2 and DNA methyltransferase 1 were detected by real-time PCR and Western blot, respectively. DNA methylation level of dimethylarginine dimethylaminohydrolase 2 was assayed by methylation specific PCR. The binding level of DNA methyltransferase 1 in the promoter of dimethylarginine dimethylaminohydrolase 2 was determined by chromatin immunoprecipitation-quantitative real-time PCR. It was shown that the apoptosis rate was decreased significantly in human umbilical vein endothelial cells treated with homocysteine compared with the control. Furthermore, the mRNA and protein level of dimethylarginine dimethylaminohydrolase 2 were downregulated, the dimethylarginine dimethylaminohydrolase 2 gene promoter was hypermethylated, and the DNA methyltransferase 1 mRNA and protein level were increased in human umbilical vein endothelial cells treated with homocysteine. Chromatin immunoprecipitation-quantitative real-time PCR revealed that homocysteine-induced binding of DNA methyltransferase 1 to the dimethylarginine dimethylaminohydrolase 2 promoter was increased. Pretreatment with epigallocatechin-3-gallate or 5-Aza inhibited such effects of homocysteine. In conclusion, epigallocatechin-3-gallate exerted protective effects on homocysteine-induced apoptosis in human umbilical vein endothelial cells by inhibiting promoter hypermethylation of the dimethylarginine dimethylaminohydrolase 2 gene and inducing dimethylarginine dimethylaminohydrolase 2 expression. These effects may be due to the decreased DNA methyltransferase 1 expression and binding of DNA methyltransferase 1 to the dimethylarginine dimethylaminohydrolase 2 promoter induced by epigallocatechin-3-gallate. This research suggests that modulating the epigenetic processes might be a novel plausible way for treatment of atherosclerosis.