Induction of microRNA-138 by pro-inflammatory Cytokines causes Endothelial Cell Dysfunction.

ArticleinFEBS letters 588(6) · January 2014with18 Reads
DOI: 10.1016/j.febslet.2014.01.033 · Source: PubMed
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.
    • "In hypertensive status, Ang II-induced miR-130a mediated VSMCs proliferation and vascular remodeling by preventing the expression of growth arrest-specific homeobox (GAX) [11] . In human microvascular endothelial cells, exposure to Ang II increased the stability of HIF1-í µí»¼ with consequent induction of miR-138, which attenuated the bioavailability of NO and mediated the proinflammatory signal transduction [26]. Eskildsen et al. [27] reported that chronic Ang II infusion enhanced the levels of miR-132/-212 in hypertensive rats, which were prevented by treatment with AT1R blocker. "
    [Show abstract] [Hide abstract] ABSTRACT: The renin-angiotensin aldosterone system (RAAS) plays a pivotal role in the development of hypertension. Angiotensin converting enzyme 2 (ACE2), which primarily metabolises angiotensin (Ang) II to generate the beneficial heptapeptide Ang-(1-7), serves as a negative regulator of the RAAS. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardiovascular protective peptide. The physiological effects of Apelin are exerted through binding to its receptor APJ, a seven-transmembrane G protein-coupled receptor that shares significant homology with the Ang II type 1 receptor (AT1R). The deregulation of microRNAs, a class of short and small noncoding RNAs, has been shown to involve cardiovascular remodeling and pathogenesis of hypertension via the activation of the Ang II/AT1R pathway. MicroRNAs are linked with modulation of the ACE2/Apelin signaling, which exhibits beneficial effects in the cardiovascular system and hypertension. The ACE2-coupled crosstalk among the RAAS, the Apelin system, and microRNAs provides an important mechanistic insight into hypertension. This paper focuses on what is known about the ACE2/Apelin signaling and its biological roles, paying particular attention to interactions and crosstalk among the ACE2/Apelin signaling, microRNAs, and hypertension, aiming to facilitate the exploitation of new therapeutic medicine to control hypertension.
    Full-text · Article · Mar 2015
    • "Most recent studies reported that downregulated miR-138 sustained inflammatory factor NF-kB activation and promotedTable 2. Predicted common targets of 2 miRNAs (Names in bold are the common targets for at least 3 miRNAs). esophageal cancer progression [42], and that miR-138 response to pro-inflammatory cytokines depends on the stabilization of HIF1- a in primary human microvascular endothelial cells [43]. miR-145 is also a tumor suppressor gene. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jun 2014
  • [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jun 2014
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