Induction of microRNA-138 by pro-inflammatory Cytokines causes Endothelial Cell Dysfunction.
ABSTRACT Exposure to pro-inflammatory cytokines, such as angiotensin II, endothelin-1 or TNF leads to endothelial dysfunction, characterized by the reduced production of nitric oxide via endothelial nitric oxide synthase (eNOS). We recently identified the Ca(2+) binding protein S100A1 as an essential factor required for eNOS activity. Here we report that pro-inflammatory cytokines down-regulate expression of S100A1 in primary human microvascular endothelial cells (HMVECs) via induction of microRNA-138 (miR-138), in a manner that depends on the stabilization of HIF1-α. We show that loss of S100A1 in ECs reduces stimulus-induced NO production, which can be prevented by inhibition of miR-138. Our study suggests that targeting miR-138 might be beneficial for the treatment of cardiovascular disease.
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ABSTRACT: Our previous studies have demonstrated that genetic deletion of the Muc2 gene causes colorectal cancers in mice. The current study further showed that at the early stage (<3 months) the Muc2 knockout mice spontaneously developed chronic inflammation in colon and rectum, similar pathological features as human colitis; and at the late stage (>3 months) the mice exhibited colorectal cancer, including a unique phenotype of rectal prolapsed (rectal severe inflammation and adenocarcinoma). Thus, the age of 3 months might be the key point of the transition from chronic inflammation to cancer. To determine the mechanisms of the malignant transformation, we conducted miRNA array on the colonic epithelial cells from the 3-month Muc2-/- and +/+ mice. MicroRNA profiling showed differential expression of miRNAs (i.e. lower or higher expression enrichments) in Muc2-/- mice. 15 of them were validated by quantitative PCR. Based on relevance to cytokine and cancer, 4 miRNAs (miR-138, miR-145, miR-146a, and miR-150) were validate and were found significantly downregulated in human colitis and colorectal cancer tissues. The network of the targets of these miRNAs was characterized, and interestedly, miRNA-associated cytokines were significantly increased in Muc2-/-mice. This is the first to reveal the importance of aberrant expression of miRNAs in dynamically transformation from chronic colitis to colitis-associated cancer. These findings shed light on revealing the mechanisms of chronic colitis malignant transformation.PLoS ONE 06/2014; 9(6):e99132. DOI:10.1371/journal.pone.0099132
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ABSTRACT: Statins effectively reduce cardiovascular disease (CVD) morbidity and mortality. However, even after low-density lipoprotein cholesterol goal attainment there is a residual CVD risk. To reduce this risk, combining statins with drugs acting on the renin-angiotensin system (RAS) was investigated. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE), Japanese Coronary Artery Disease (JCAD), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and The Assessing the Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) trials suggest that the statin plus RAS inhibition combination reduces CVD events more than a statin alone and considerably more than RAS inhibition alone. This benefit seems to be related to effects on endothelial function, vascular inflammation and the initiation, progression and rupture of atheromatous plaques. These effects are, at least in part, driven by mediators, the microRNAs (miRs), that are implicated in the pathogenesis and clinical manifestations of atherosclerosis (e.g. restoration of endothelial function and attenuation of vascular inflammation). Some miRs are favourably affected by statins and others by RAS inhibition. There is a miR family (miR-146a/b), related to coronary artery plaque destabilization that is beneficially affected by both statins and RAS inhibition. Statins and RAS inhibition combination should be routinely prescribed in high risk patients with CVD, hypertension, obesity, metabolic syndrome, and/or diabetes to maximize clinical benefit.Current Pharmaceutical Design 06/2014; DOI:10.2174/1381612820666140620115756
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ABSTRACT: Pulmonary arterial hypertension (PAH) is a severe and increasingly prevalent disease, manifested by the maladaptation of pulmonary vasculature, which consequently leads to right heart failure and possibly even death. The development of PAH is characterized by specific functional as well as structural changes, primarily associated with the aberrant function of the pulmonary artery endothelial cells, smooth muscle cells, and vascular fibroblasts. MicroRNAs constitute a class of small ≈22-nucleotides-long non-coding RNAs that post-transcriptionally regulate gene expression and that may lead to significant cell proteome changes. While the involvement of miRNAs in the development of various diseases-especially cancer-has been reported, numerous miRNAs have also been associated with PAH onset, progression, or treatment responsiveness. This review focuses on the role of microRNAs in the development of PAH as well as on their potential use as biomarkers and therapeutic tools in both experimental PAH models and in humans. Special attention is given to the roles of miR-21, miR-27a, the miR-17-92 cluster, miR-124, miR-138, the miR-143/145 cluster, miR-150, miR-190, miR-204, miR-206, miR-210, miR-328, and the miR-424/503 cluster, specifically with the objective of providing greater insight into the pervasive roles of miRNAs in the pathogenesis of this deadly condition. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.Journal of the American Society of Hypertension (JASH) 12/2014; 9(3). DOI:10.1016/j.jash.2014.12.011