miRNAs and lncRNAs in vascular injury and remodeling

Vascular injury, remodeling, as well as angiogenesis, are the leading causes of coronary or cerebrovascular disease. The blood vessel functional imbalance trends to induce atherosclerosis, hypertension, and pulmonary arterial hypertension. As several genes have been identified to be dynamically regulated during vascular injury and remodeling, it is becoming widely accepted that several types of non-coding RNA, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are involved in regulating the endothelial cell and vascular smooth muscle cell (VSMC) behaviors. Here, we review the progress of the extant studies on mechanistic, clinical and diagnostic implications of miRNAs and lncRNAs in vascular injury and remodeling, as well as angiogenesis, emphasizing the important roles of miRNAs and lncRNAs in vascular diseases. Furthermore, we introduce the interaction between miRNAs and lncRNAs, and highlight the mechanism through which lncRNAs are regulating the miRNA function. We envisage that continuous in-depth research of non-coding RNAs in vascular disease will have significant implications for the treatment of coronary or cerebrovascular diseases.     

Wnt5a及其信号通路与血管新生的研究进展

Wnt5a是Wnt蛋白家族中的成员之一,在细胞成熟、胚胎发育等过程中发挥着重要作用。研究表明Wnt5a的表达调控及其信号通路与血管新生密切相关,并且在血管新生性相关疾病中发挥了重要作用。本文从Wnt5a与其相关信号转导通路对血管新生的影响以及分子机制等方面进行阐述和展望,旨在为以Wnt5a为靶点进行血管新生性疾病的防治提供理论依据。     

microRNAs参与动脉粥样硬化疾病的发生

microRNAs (miRNAs)是一类非编码的小分子RNA（～22 nt）,可在转录后水平调控基因表达.miRNAs参与调控机体的多种生理和病理过程.近来研究表明,miRNAs可能与动脉粥样硬化疾病的发生和发展密切相关,在血管新生、炎症和脂蛋白代谢等方面发挥了关键作用.本文就miRNAs与动脉粥样硬化疾病相关的研究进展进行综述,为研究miRNAs在动脉粥样硬化的发病机制中的作用,以及为miRNAs能够作为诊断动脉粥样硬化疾病的生物标志物提供思路.     

MicroRNAs as a therapeutic target for cardiovascular diseases

MicroRNAs (miRNAs) are tiny, endogenous, conserved, non-coding RNAs that negatively modulate gene expression by either promoting the degradation of mRNA or down-regulating the protein production by translational repression. They maintain optimal dose of cellular proteins and thus play a crucial role in the regulation of biological functions. Recent discovery of miRNAs in the heart and their differential expressions in pathological conditions provide glimpses of undiscovered regulatory mechanisms underlying cardiovascular diseases. Nearly 50 miRNAs are overexpressed in mouse heart. The implication of several miRNAs in cardiovascular diseases has been well documented such as miRNA-1 in arrhythmia, miRNA-29 in cardiac fibrosis, miRNA-126 in angiogenesis and miRNA-133 in cardiac hypertrophy. Aberrant expression of Dicer (an enzyme required for maturation of all miRNAs) during heart failure indicates its direct involvement in the regulation of cardiac diseases. MiRNAs and Dicer provide a particular layer of network of precise gene regulation in heart and vascular tissues in a spatiotemporal manner suggesting their implications as a powerful intervention tool for therapy. The combined strategy of manipulating miRNAs in stem cells for their target directed differentiation and optimizing the mode of delivery of miRNAs to the desired cells would determine the future potential of miRNAs to treat a disease. This review embodies the recent progress made in microRNomics of cardiovascular diseases and the future of miRNAs as a potential therapeutic target - the putative challenges and the approaches to deal with it.     

Role of specific microRNAs for endothelial function and angiogenesis

Accumulating evidence indicates that various aspects of angiogenesis, such as proliferation, migration, and morphogenesis of endothelial cells, can be regulated by specific miRNAs in an endothelial-specific manner. As novel molecular targets, miRNAs have a potential value for treatment of angiogenesis-associated diseases such as cancers, inflammation, and vascular diseases. In this article, we review the latest advances in the identification and validation of angiogenesis-regulatory miRNAs and their targets, and discuss their roles and mechanisms in regulating endothelial cell function and angiogenesis.     

NDAMDA: Network distance analysis for MiRNA‐disease association prediction

In recent years, microRNAs (miRNAs) are attracting an increasing amount of researchers’ attention, as accumulating studies show that miRNAs play important roles in various basic biological processes and that dysregulation of miRNAs is connected with diverse human diseases, particularly cancers. However, the experimental methods to identify associations between miRNAs and diseases remain costly and laborious. In this study, we developed a computational method named Network Distance Analysis for MiRNA‐Disease Association prediction (NDAMDA) which could effectively predict potential miRNA‐disease associations. The highlight of this method was the use of not only the direct network distance between 2 miRNAs (diseases) but also their respective mean network distances to all other miRNAs (diseases) in the network. The model's reliable performance was certified by the AUC of 0.8920 in global leave‐one‐out cross‐validation (LOOCV), 0.8062 in local LOOCV and the average AUCs of 0.8935 ± 0.0009 in fivefold cross‐validation. Moreover, we applied NDAMDA to 3 different case studies to predict potential miRNAs related to breast neoplasms, lymphoma, oesophageal neoplasms, prostate neoplasms and hepatocellular carcinoma. Results showed that 86%, 72%, 86%, 86% and 84% of the top 50 predicted miRNAs were supported by experimental association evidence. Therefore, NDAMDA is a reliable method for predicting disease‐related miRNAs.     

SNMDA: A novel method for predicting microRNA‐disease associations based on sparse neighbourhood

miRNAs are a class of small noncoding RNAs that are associated with a variety of complex biological processes. Increasing studies have shown that miRNAs have close relationships with many human diseases. The prediction of the associations between miRNAs and diseases has thus become a hot topic. Although traditional experimental methods are reliable, they could only identify a limited number of associations as they are time‐consuming and expensive. Consequently, great efforts have been made to effectively predict reliable disease‐related miRNAs based on computational methods. In this study, we present a novel approach to predict the potential microRNA‐disease associations based on sparse neighbourhood. Specifically, our method takes advantage of the sparsity of the miRNA‐disease association network and integrates the sparse information into the current similarity matrices for both miRNAs and diseases. To demonstrate the utility of our method, we applied global LOOCV, local LOOCV and five‐fold cross‐validation to evaluate our method, respectively. The corresponding AUCs are 0.936, 0.882 and 0.934. Three types of case studies on five common diseases further confirm the performance of our method in predicting unknown miRNA‐disease associations. Overall, results show that SNMDA can predict the potential associations between miRNAs and diseases effectively.     

MCLPMDA: A novel method for miRNA‐disease association prediction based on matrix completion and label propagation

MiRNAs are a class of small non‐coding RNAs that are involved in the development and progression of various complex diseases. Great efforts have been made to discover potential associations between miRNAs and diseases recently. As experimental methods are in general expensive and time‐consuming, a large number of computational models have been developed to effectively predict reliable disease‐related miRNAs. However, the inherent noise and incompleteness in the existing biological datasets have inevitably limited the prediction accuracy of current computational models. To solve this issue, in this paper, we propose a novel method for miRNA‐disease association prediction based on matrix completion and label propagation. Specifically, our method first reconstructs a new miRNA/disease similarity matrix by matrix completion algorithm based on known experimentally verified miRNA‐disease associations and then utilizes the label propagation algorithm to reliably predict disease‐related miRNAs. As a result, MCLPMDA achieved comparable performance under different evaluation metrics and was capable of discovering greater number of true miRNA‐disease associations. Moreover, case study conducted on Breast Neoplasms further confirmed the prediction reliability of the proposed method. Taken together, the experimental results clearly demonstrated that MCLPMDA can serve as an effective and reliable tool for miRNA‐disease association prediction.     

MicroRNA‐125b in vascular diseases: An updated systematic review of pathogenetic implications and clinical applications

Epigenetic changes, particularly non‐coding RNAs, have been implicated extensively in the pathogenesis of vascular diseases. Specific miRNAs are involved in the differentiation, phenotypic switch, proliferation, apoptosis, cytokine production and matrix deposition of endothelial cells and/or vascular smooth muscle cells. MicroRNA‐125b has been studied in depth for its role in carcinogenesis with a double‐edged role; that is, it can act as an oncogene in some cancer types and as a tumour suppressor gene in others. However, cumulative evidence from the use of advanced miRNA profiling techniques and bioinformatics analysis suggests that miR‐125b can be a potential mediator and useful marker of vascular diseases. Currently, the exact role of miR‐125b in vascular diseases is not known. In this systematic review, we intend to provide an updated compilation of all the recent findings of miR‐125b in vascular diseases, using a systematic approach of retrieving data from all available reports followed by data summarization. MiR‐125b serves as a pathogenic player in multiple vascular pathologies involving endothelia and vascular smooth muscle cells and also serves as a diagnostic marker for vascular diseases. We further provide a computational biologic presentation of the complex network of miR‐125b and its target genes within the scope of vascular diseases.     

microRNA-378 与肿瘤血管生成的研究进展

微小RNA(MicroRNAs,mi RNAs)是真核生物中一类长度约为21到23个核苷酸的非编码小分子单链RNA。mi RNA通过与靶m RNA 3′UTR(3′-untranslated region,3′非编码区)完全或不完全结合,抑制翻译或直接诱导其降解,发挥转录后负调控作用。mi RNA参与机体多种生理和病理过程,且可通过调控其靶标基因参与各种信号通路,影响血管生成。mi R-378属于诸多mi RNAs中的一种。目前已知mi R-378的研究主要集中在肿瘤发生及血管生成、心血管疾病和脑缺血等病理过程,其中与肿瘤发生及血管生成相关研究居多。mi R-378在不同肿瘤中的发挥的作用也不一样,在脑胶质瘤,肺癌,横纹肌肉瘤等肿瘤中发挥促癌基因的作用,在卵巢癌,胃癌,大肠癌等肿瘤中发挥抑癌基因的作用。但是,mi R-378调节肿瘤血管生成的作用机制还有待于深入研究。本文主要对mi R-378在四种肿瘤(脑胶质瘤、肺腺癌、卵巢癌和横纹肌肉瘤)中调控血管生成的相关性研究进展进行综述,以期为这些疾病的治疗和预防提供一种新的思路。     

Peritoneal Fluid Reduces Angiogenesis-Related MicroRNA Expression in Cell Cultures of Endometrial and Endometriotic Tissues from Women with Endometriosis

Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent gynecological diseases. It has been suggested that modifications of both endometrial and peritoneal factors could be implicated in this disease. Endometriosis is a multifactorial disease in which angiogenesis and proteolysis are dysregulated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the protein expression and may be the main regulators of angiogenesis. Our hypothesis is that peritoneal fluid from women with endometriosis could modify the expression of several miRNAs that regulate angiogenesis and proteolysis in the endometriosis development. The objective of this study has been to evaluate the influence of endometriotic peritoneal fluid on the expression of six miRNAs related to angiogenesis, as well as several angiogenic and proteolytic factors in endometrial and endometriotic cell cultures from women with endometriosis compared with women without endometriosis.

Methods

Endometrial and endometriotic cells were cultured and treated with endometriotic and control peritoneal fluid pools. We have studied the expression of six miRNAs (miR-16, -17-5p, -20a, -125a, -221, and -222) by RT-PCR and protein and mRNA levels of vascular endothelial growth factor-A, thrombospondin-1, urokinase plasminogen activator and plasminogen activator inhibitor-1 by ELISA and qRT-PCR respectively.

Results

Control and endometriotic peritoneal fluid pools induced a significant reduction of all miRNAs levels in endometrial and endometriotic cell cultures. Moreover, both peritoneal fluids induced a significant increase in VEGF-A, uPA and PAI-1 protein levels in all cell cultures without significant increase in mRNA levels. Endometrial cell cultures from patients treated with endometriotic peritoneal fluid showed lower expression of miRNAs and higher expression of VEGF-A protein levels than cultures from controls. In conclusion, this “in vitro” study indicates that peritoneal fluid from women with endometriosis modulates the expression of miRNAs that could contribute to the angiogenic and proteolytic disequilibrium observed in this disease.     

In silico prediction of potential miRNA‐disease association using an integrative bioinformatics approach based on kernel fusion

Accumulating experimental evidence has demonstrated that microRNAs (miRNAs) have a huge impact on numerous critical biological processes and they are associated with different complex human diseases. Nevertheless, the task to predict potential miRNAs related to diseases remains difficult. In this paper, we developed a Kernel Fusion‐based Regularized Least Squares for MiRNA‐Disease Association prediction model (KFRLSMDA), which applied kernel fusion technique to fuse similarity matrices and then utilized regularized least squares to predict potential miRNA‐disease associations. To prove the effectiveness of KFRLSMDA, we adopted leave‐one‐out cross‐validation (LOOCV) and 5‐fold cross‐validation and then compared KFRLSMDA with 10 previous computational models (MaxFlow, MiRAI, MIDP, RKNNMDA, MCMDA, HGIMDA, RLSMDA, HDMP, WBSMDA and RWRMDA). Outperforming other models, KFRLSMDA achieved AUCs of 0.9246 in global LOOCV, 0.8243 in local LOOCV and average AUC of 0.9175 ± 0.0008 in 5‐fold cross‐validation. In addition, respectively, 96%, 100% and 90% of the top 50 potential miRNAs for breast neoplasms, colon neoplasms and oesophageal neoplasms were confirmed by experimental discoveries. We also predicted potential miRNAs related to hepatocellular cancer by removing all known related miRNAs of this cancer and 98% of the top 50 potential miRNAs were verified. Furthermore, we predicted potential miRNAs related to lymphoma using the data set in the old version of the HMDD database and 80% of the top 50 potential miRNAs were confirmed. Therefore, it can be concluded that KFRLSMDA has reliable prediction performance.     

GIMDA: Graphlet interaction‐based MiRNA‐disease association prediction

MicroRNAs (miRNAs) have been confirmed to be closely related to various human complex diseases by many experimental studies. It is necessary and valuable to develop powerful and effective computational models to predict potential associations between miRNAs and diseases. In this work, we presented a prediction model of Graphlet Interaction for MiRNA‐Disease Association prediction (GIMDA) by integrating the disease semantic similarity, miRNA functional similarity, Gaussian interaction profile kernel similarity and the experimentally confirmed miRNA‐disease associations. The related score of a miRNA to a disease was calculated by measuring the graphlet interactions between two miRNAs or two diseases. The novelty of GIMDA lies in that we used graphlet interaction to analyse the complex relationships between two nodes in a graph. The AUCs of GIMDA in global and local leave‐one‐out cross‐validation (LOOCV) turned out to be 0.9006 and 0.8455, respectively. The average result of five‐fold cross‐validation reached to 0.8927 ± 0.0012. In case study for colon neoplasms, kidney neoplasms and prostate neoplasms based on the database of HMDD V2.0, 45, 45, 41 of the top 50 potential miRNAs predicted by GIMDA were validated by dbDEMC and miR2Disease. Additionally, in the case study of new diseases without any known associated miRNAs and the case study of predicting potential miRNA‐disease associations using HMDD V1.0, there were also high percentages of top 50 miRNAs verified by the experimental literatures.     

Angiogenesis and Vascular Remodeling in Chronic Airway Diseases

Asthma and chronic obstructive pulmonary disease remain a global health problem, with increasing morbidity and mortality. Despite differences in the causal agents, both diseases exhibit various degrees of inflammatory changes, structural alterations of the airways leading to airflow limitation. The existence of transient disease phenotypes which overlap both diseases and which progressively decline the lung function has complicated the search for an effective therapy. Important characteristics of chronic airway diseases include airway and vascular remodeling, of which the molecular mechanisms are complex and poorly understood. Recently, we and others have shown that airway smooth muscle (ASM) cells are not only structural and contractile components of airways, rather they bear capabilities of producing large number of pro-inflammatory and mitogenic factors. Increase in size and number of blood vessels both inside and outside the smooth muscle layer as well as hyperemia of bronchial vasculature are contributing factors in airway wall remodeling in patients with chronic airway diseases, proposing for the ongoing mechanisms like angiogenesis and vascular dilatation. We believe that vascular changes directly add to the airway narrowing and hyper-responsiveness by exudation and transudation of proinflammatory mediators, cytokines and growth factors; facilitating trafficking of inflammatory cells; causing oedema of the airway wall and promoting ASM accumulation. One of the key regulators of angiogenesis, vascular endothelial growth factor in concerted action with other endothelial mitogens play pivotal role in regulating bronchial angiogenesis. In this review article we address recent advances in pulmonary angiogenesis and remodelling that contribute in the pathogenesis of chronic airway diseases.     

miR-15b在内皮细胞的功能及其与血管相关性疾病的关系

微小RNA(MicroRNA, miRNA)是长度为22个核苷酸的小片段非编码RNA,作为RNA干扰的参与者之一,其通过在转录后水平调节各种基因的表达,进而对细胞的生命活动产生广泛影响。miR-15b是miR-15/16家族一员,是一类在机体各系统、特别是血管内皮系统广泛表达的微小RNA,主要影响细胞的增殖、凋亡、侵袭、成管等行为。文章主要对miR-15b及相关家族成员在各类细胞、特别是血管内皮细胞的生物学行为、作用机制及miR-15b在心血管相关疾病的发生、发展及预后等过程中的作用进行了详细阐述。同时,文章对miR-15b相关家族成员在以胎盘内皮发育异常为病理基础的妊娠期高血压疾病如子痫前期的发病机制中的作用进行了探讨。     

Delivery of growth factor‐based therapeutics in vascular diseases: Challenges and strategies

Either cardiovascular or peripheral vascular diseases have become the major cause of morbidity and mortality worldwide. Recently, growth factors therapeutics, whatever administrated in form of exogenous growth factors or their relevant genes have been discovered to be an effective strategy for the prevention and therapy of vascular diseases, because of their promoting angiogenesis. Besides, as an alternative, stem cell‐based therapy has been also developed in view of their paracrine‐mediated effect or ability of differentiation toward angiogenesis‐related cells under assistance of growth factors. Despite of being specific and potent, no matter growth factors or stem cells‐based therapy, their full clinical transformation is limited from bench to bedside. In this review, the potential choices of therapeutic modes based on types of different growth factors or stem cells were firstly summarized for vascular diseases. The confronted various challenges such as lack of non‐invasive delivery method, the physiochemical challenge, the short half‐life time, and poor cell survival, were carefully analyzed for these therapeutic modes. Various strategies to overcome these limitations are put forward from the perspective of drug delivery. The expertised design of a suitable delivery form will undoubtedly provide valuable insight into their clinical application in the regenerative medicine.     

Systemic effects of Wnt signaling

Wnt signaling plays a key role in several physiological and pathological aspects. Even if Wnt signal was first described more than 20 years ago, its role in systemic effects, such as angiogenesis and vascular disorders, bone biology, autoimmune diseases, neurological diseases, and neoplastic disorders, was only recently emerged through the use of animal and in vitro models. Moreover, Wnt signaling inhibitors, such as DKK‐1, may be advantageously considered targets for the treatment of several diseases, including osteoporosis, vascular diseases, inflammatory diseases, neurological diseases, and cancer. Nevertheless, further studies are required to provide a complete understanding of this complex signaling pathway, and especially of its role in human diseases, considering the possible advantageous effects of Wnt signaling inhibitors on the progression of disease conditions. J. Cell. Physiol. 228: 1428–1432, 2013. © 2013 Wiley Periodicals, Inc.