Epigenetic repression of THBD transcription by BRG1 contributes to deep vein thrombosis.

BACKGROUND: Deep vein thrombosis (DVT) with its major complication, pulmonary embolism, is a global health problem. Endothelial dysfunction is involved in the pathogenesis of DVT. We have previously demonstrated that endothelial specific deletion of Brahma-related gene 1 (BRG1) ameliorates atherosclerosis and aneurysm in animal models. Whether endothelial BRG1 contributes to DVT development remains undetermined. METHODS: DVT was induced in mice by ligation of inferior vena cava. Deletion of BRG1 in endothelial cells was achieved by crossing the Cdh5-ERT-Cre mice with the Brg1loxp/loxp mice. RESULTS: Here we report that compared to the wild type mice, BRG1 conditional knockout (CKO) mice displayed substantially decreased DVT susceptibility characterized by decreased weight and size of thrombus and reduced immune infiltration. In endothelial cells, thrombomodulin (THBD) expression was significantly decreased by TNF-α stimulation, while BRG1 knockdown or inhibition recovered THBD expression. Further analysis revealed that BRG1 deficiency decreased the CpG methylation levels of the THBD promoter induced by TNF-α. Mechanistically, BRG1 directly upregulated DNMT1 expression after TNF-α treatment in endothelial cells. More importantly, administration of a small-molecule BRG1 inhibitor PFI-3 displayed potent preventive and therapeutic potentials in the DVT model. CONCLUSIONS: Our findings implicate BRG1 as an important regulator of DVT pathogenesis likely through epigenetic regulation of THBD expression in endothelial cells and provide translational proof-of-concept for targeting BRG1 in DVT intervention.

Effects of coenzyme Q10 supplementation on statin-induced myopathy: a meta-analysis of randomized controlled trials.

BACKGROUND: Statins can trigger a series of muscle-related adverse events, commonly referred to collectively as statin-induced myopathy. Although coenzyme Q10 (CoQ10) is widely used as a supplement in statin therapy, there is little clinical evidence for this practice. AIM: This study aims to assess the effect of adding CoQ10 on statin-induced myopathy. METHODS: Searching the PubMed, EMBASE, and the Cochrane Library databases to identify randomized controlled trials investigating the effect of adding CoQ10 on creatine kinase (CK) activity and degree of muscle pain as two indicators of statin-induced myopathy. Two reviewers will independently extract data from the included articles. RESULTS: Study screening included a randomized controlled trial of oral CoQ10 versus placebo in patients with statin-induced myopathy. We had a total of 8 studies in which 472 patients were treated with statins: 6 studies with 281 participants assessed the impact of adding CoQ10 on CK activity, and 4 studies with 220 participants were included to evaluate the impacts of CoQ10 addition on muscle pain. Compared with the controls, CK activity increased after adding CoQ10, but the change was not significant (mean difference, 3.29 U/L; 95% CI, - 29.58 to 36.17 U/L; P = 0.84). Similarly, the meta-analysis did not benefit CoQ10 over placebo in improving muscle pain (standardized mean difference, - 0.59; 95% CI, - 1.54 to 0.36; P = 0.22). CONCLUSION: The outcomes of this meta-analysis of existing randomized controlled trials showed that supplementation with CoQ10 did not have any significant benefit in improving statin-induced myopathy.

Corrigendum: An MRTF-A-Sp1-PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy.

[This corrects the article DOI: 10.3389/fcell.2020.00839.].

An MRTF-A-Sp1-PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy.

Cardiac hypertrophy is a critical intermediate step in the pathogenesis of heart failure. A myriad of signaling networks converge on cardiomyocytes to elicit hypertrophic growth in response to various injurious stimuli. In the present study, we investigated the cardiomyocyte-specific role of myocardin-related transcription factor A (MRTF-A) in angiotensin-II (Ang-II)-induced cardiac hypertrophy and the underlying mechanism. We report that conditional MRTF-A deletion in cardiomyocytes attenuated Ang-II-induced cardiac hypertrophy in mice. Similarly, MRTF-A knockdown or inhibition suppressed Ang-II-induced prohypertrophic response in cultured cardiomyocytes. Of note, Ang II treatment upregulated expression of phosphodiesterase 5 (PDE5), a known mediator of cardiac hypertrophy and heart failure, in cardiomyocytes, which was blocked by MRTF-A depletion or inhibition. Mechanistically, MRTF-A activated expression of specificity protein 1 (Sp1), which in turn bound to the PDE5 promoter and upregulated PDE5 transcription to promote hypertrophy of cardiomyocytes in response to Ang II stimulation. Therefore, our data unveil a novel MRTF-A-Sp1-PDE5 axis that mediates Ang-II-induced hypertrophic response in cardiomyocytes. Targeting this newly identified MRTF-A-Sp1-PDE5 axis may yield novel interventional solutions against heart failure.

Efficacy and safety of drug-eluting stenting compared with bypass grafting in diabetic patients with multivessel and/or left main coronary artery disease.

Although percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) and bypass grafting are generally believed to be superior revascularization strategies in patients with coronary artery disease (CAD), the optimal strategy for diabetic patients is still controversial. This meta-analysis was performed to compare two methods of revascularization for patients with diabetes mellitus with left main coronary artery lesions or disease in multiple coronary arteries. Compared with the coronary artery bypass grafting (CABG) group, those receiving PCI-DES showed a greater risk of major adverse cardiovascular events (MACEs) (hazard ratio [HR]: 1.12, 95% confidence interval [CI]: 1.01-1.25, P = 0.03), major adverse cardiac and cerebrovascular events (MACCEs) (HR: 1.85, 95% CI: 1.58-2.16; P < 0.001), stroke (HR: 1.15, 95% CI: 1.02-1.29, P = 0.02), myocardial infarction (MI) (HR: 1.48, 95% CI: 1.04-2.09, P = 0.03), and repeat revascularization (HR: 3.23, 95% CI: 1.37-7.59, P = 0.007). CABG for diabetic patients with multivessel and/or left main CAD was superior to PCI-DES with regard to MACEs, MACCEs, MI, repeat revascularization and stroke, but there was no clear difference in all-cause mortality.

Surface Structure Dependence of Mechanochemical Etching: Scanning Probe-Based Nanolithography Study on Si(100), Si(110), and Si(111).

We employed a scanning probe-based lithography process on single-crystalline Si(100), Si(110), and Si(111) surfaces and studied the effects of crystallographic surface structures on mechanochemical etching of silicon in liquid water. The facet angle and etching rate of the mechanochemical process were different from those of the purely chemical etching process. In liquid water, the shape of the mechanochemically etched nanochannel appeared to be governed by thermodynamics of the etched surface, rather than stress distribution. Analyzing the etch rate with the mechanically assisted Arrhenius-type kinetics model showed that the shear-induced hydrolysis activity varies drastically with the crystallographic structure of silicon surface.

Exploring Molecules beyond CO as Tip Functionalizations in High-Resolution Noncontact Atomic Force Microscopy: A First Principles Approach.

Atomic resolution of molecules has been achieved using noncontact atomic force microscopy (AFM) with the key step to functionalize the tip apex by attaching suitable molecules so as to achieve high spatial resolution through a sharper tip. A few molecular terminations have been explored theoretically and experimentally, and they exhibit various imaging behaviors. Here, we explore the influence of the structures and chemical compositions of various molecular candidates as tips on the contrast of AFM images by a first principles approach. Our results reveal that the two end atoms of a linear molecule terminating nearest the sample dominate the imaging behaviors, for example, atomic resolution, sharpness, distortion, and so forth, whereas the symmetry of the termination plays an important role in the distortion of AFM images. These findings suggest that new tip terminations can be engineered by decoupling the three end atoms responsible for imaging behaviors from the tip structure behind them, which is attached to the macro tip apex.