细胞微泡miRNA对内皮细胞的调控

<正>内皮细胞是内衬在血管内壁表面的单细胞层,在调节血管功能及维持机体内环境稳态等方面发挥重要作用。内皮细胞活化或损伤与诸多疾病相关,如高血压、动脉粥样硬化、冠心病等心血管疾病及肿瘤、糖尿病等。近年研究发现细胞微泡(microparticles,MPs)是参与内皮细胞损伤过程的重要因素,并在很多疾病的发生发展中发挥作用。最近对血浆中与细胞微泡中的微小RNA(microRNA,miRNA)含量     

MicroRNA-133b regulates the growth and migration of vascular smooth muscle cells by targeting matrix metallopeptidase 9

Atherosclerosis is a systemic disease affecting the whole arterial tree of the human body, and it is the leading cause of cardiovascular diseases.Vascular smooth muscle cells (VSMCs) have been identified to play a key role in the development of atherosclerosis. MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs, and they play a critical role in many biological processes including regulating cell proliferation, migration and apoptosis. However, till now, the expression and role of miR-133b in atherosclerosis remain largely unknown. Therefore, our purpose was to investigate the expression and role of miR-133b in atherosclerosis and to explore the underlying mechanism. The results showed that miR-133b was down-regulated in the blood and vascular plaque tissues of rabbits with atherosclerosis. Matrix metallopeptidase 9 (MMP-9) was a direct target of miR-133b. In addition, our data indicated that miR-133b mimic could significantly inhibit rVSMC cell proliferation activity, migration ability and induce cell apoptosis compared with the control group, and all these effects were reversed by MMP-9-plasmid. Taken together, these findings highlight an important role for miR-133b/MMP-9 axis in atherosclerosis. And miR-133b might be a valuable clinical marker and therapeutic target for atherosclerosis.     

Emerging role of Piezo ion channels in cardiovascular development

Mechanical cues are crucial for vascular development and the proper differentiation of various cell types. Piezo1 and Piezo2 are mechanically activated cationic channels expressed in various cell types, especially in vascular smooth muscle and endothelial cells. It is present as a transmembrane homotrimeric complex, regulating calcium influx. Local blood flow associated shear stress, in addition to blood pressure associated cell membrane stretching are key Piezo channel activators. There is rising proof, showcasing Piezo channels significance in myocytes, cardiac fibroblast, vascular tone maintenance, atherosclerosis, hypertension, NO generation, and baroreceptor reflex. Here, we review the role of Piezo channels in cardiovascular development and its associated clinical disorders. Also, emphasizing on Piezo channel modulators which might lead to novel therapies for cardiovascular diseases.     

血管老化在动脉粥样硬化中的研究进展

血管老化是血管的结构和功能随年龄增长呈现年龄依赖性的退行性改变,可导致心血管疾病的患病风险显著增加.动脉粥样硬化是多种心血管疾病的病理生理基础,血管老化在动脉粥样硬化的发生发展中发挥重要作用.有效评估血管老化对动脉粥样硬化性心血管疾病的临床诊疗意义重大.本文总结了血管老化的结构和功能性变化,阐述血管老化过程中血管细胞端...     

Potential role of blood microRNAs as non-invasive biomarkers for early detection of asymptomatic coronary atherosclerosis in obese children with metabolic syndrome

The pandemic of the childhood obesity represent a major public health problem all over the world. This leads to detection of many health conditions that were previously considered an adulthood diseases. The rise in the prevalence of the obesity and overweight among children means that the world will face an explosion in the prevalence of the metabolic syndrome (MS), which increases the risk of atherosclerotic disease and death in adulthood. The atherosclerotic process has proved to develop silently for decades during childhood and adolescence before the cardiovascular complications such as myocardial infarction and stroke occur. This means that obese children especially with MS could have heart attacks and suffer from heart disease in an age when they should be very healthy, but most of these data either derived from autopsy findings or studies that confirmed the presence of peripheral atherosclerosis. Very early detection of coronary atherosclerosis in obese children with metabolic syndrome through a non invasive method will be of great importance, allowing for early therapeutic intervention. The discovery of microRNAs (miRNAs) is considered a major scientific breakthrough in the last years; recent studies have suggested a potentially important role of miRNAs in the control of diversity aspects of cardiac functions in health and disease including coronary atherosclerosis. Moreover, circulating miRNAs profiles recently used as a non-invasive biomarker for diagnosis of multiple cardiovascular diseases. The identification of distinct circulating miRNA profiles may impact the development of specific miRNAs as biomarkers in pediatric cardiovascular diseases. Therefore, we postulate that some of these circulating miRNAs may be a potential biomarker for early non-invasive diagnosis of coronary atherosclerosis in very early asymptomatic stage in obese children with metabolic syndrome, giving an excellent chance to fight against the first killer in the adult population in childhood period.     

Potential role of blood microRNAs as non-invasive biomarkers for early detection of asymptomatic coronary atherosclerosis in obese children with metabolic syndrome

The pandemic of the childhood obesity represent a major public health problem all over the world. This leads to detection of many health conditions that were previously considered an adulthood diseases. The rise in the prevalence of the obesity and overweight among children means that the world will face an explosion in the prevalence of the metabolic syndrome (MS), which increases the risk of atherosclerotic disease and death in adulthood. The atherosclerotic process has proved to develop silently for decades during childhood and adolescence before the cardiovascular complications such as myocardial infarction and stroke occur. This means that obese children especially with MS could have heart attacks and suffer from heart disease in an age when they should be very healthy, but most of these data either derived from autopsy findings or studies that confirmed the presence of peripheral atherosclerosis. Very early detection of coronary atherosclerosis in obese children with metabolic syndrome through a non invasive method will be of great importance, allowing for early therapeutic intervention. The discovery of microRNAs (miRNAs) is considered a major scientific breakthrough in the last years; recent studies have suggested a potentially important role of miRNAs in the control of diversity aspects of cardiac functions in health and disease including coronary atherosclerosis. Moreover, circulating miRNAs profiles recently used as a non-invasive biomarker for diagnosis of multiple cardiovascular diseases. The identification of distinct circulating miRNA profiles may impact the development of specific miRNAs as biomarkers in pediatric cardiovascular diseases. Therefore, we postulate that some of these circulating miRNAs may be a potential biomarker for early non-invasive diagnosis of coronary atherosclerosis in very early asymptomatic stage in obese children with metabolic syndrome, giving an excellent chance to fight against the first killer in the adult population in childhood period.     

miR-21对血管内皮功能及血管生成调节作用的研究进展

<正>血管内皮细胞作为血管的内衬,一方面参与构成血管的通透性屏障,调节液体、气体及生物大分子物质的选择性通透;另一方面可分泌大量血管活性因子,参与对凝血与抗凝功能、纤溶系统和炎症发生发展等的调控,与血管功能和循环系统的稳定密切相关。研究表明,血管内皮细胞功能激活是血管生成的先决条件~([1])。血管内皮细胞在多种细胞因子的诱导下增殖迁移,为血管管腔形成提供内皮细胞数量的积累。血管生成因子与内皮细胞受体结合可激     

Oxidative stress impairs endothelial progenitor cell function

Circulating endothelial progenitor cells (EPCs) in adult human peripheral blood were identified in 1997. Since their original identification, EPCs have been extensively studied as biomarkers to assess the risk of cardiovascular disease in human subjects and as a potential cell therapeutic for vascular regeneration. EPCs are exposed to oxidative stress during vascular injury as residents of blood vessel walls or as circulating cells homing to sites of neovascularization. Given the links between oxidative injury, endothelial cell dysfunction, and vascular disease, recent investigation has focused on the responses of EPCs to oxidant stress and the molecular mechanisms that control redox regulation in these specialized cells. In this review, we discuss the various cell and flow-cytometric techniques used to define and isolate EPCs from circulating blood and the current human and mouse genetic data, which offer insights into redox control in EPC biology and angiogenesis. Finally, we review how EPC responses to oxidant stress may be a critical determinant in maintaining the integrity and function of the cardiovascular system and how perturbations of redox control in EPCs may lead to various human diseases.     

Insights into the redox control of blood coagulation: role of vascular NADPH oxidase-derived reactive oxygen species in the thrombogenic cycle

Various cardiovascular diseases including thrombosis, atherosclerosis, (pulmonary) hypertension and diabetes, are associated with disturbed coagulation. Alterations in the vessel wall common to many cardiovascular disorders have been shown to initiate the activity of the coagulation system, but also to be the result of an abnormal coagulation system. The primary link between the coagulation and the vascular system appears to be tissue factor (TF), which is induced on the surface of vascular cells and initiates the extrinsic pathway of the blood coagulation cascade, leading to the formation of thrombin. Thrombin can also interact with the vascular wall via specific receptors and can increase vascular TF expression. Such a "thrombogenic cycle" may be essentially involved in the pathogenesis of cardiovascular disorders associated with an abnormal coagulation. Therefore, the identification of the signaling pathways regulating this cycle and each of its relevant connecting links is of fundamental importance for the understanding of these disorders and their putative therapeutic potential. Reactive oxygen species (ROS) and the ROS-generating NADPH oxidases have been shown to play important roles as signaling molecules in the vasculature. In this review, we summarize the data supporting a substantial role of ROS in promoting a thrombogenic cycle in the vascular system.     

微小RNA与血管钙化

血管钙化是糖尿病、慢性肾疾病、高血压病等普遍存在的病理改变,与心血管疾病的高发病率和病死率密切相关。近来发现微小RNA（microRNA,miRNA）能够通过调控血管平滑肌细胞的表型改变从而影响血管钙化的发生和发展。本文综述miRNA在调节血管平滑肌细胞的表型改变及血管钙化方面的新进展,并探讨miRNA作为血管钙化诊断标志分子和治疗靶点应用于临床的可能。     

MicroRNAs in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic, inflammatory, autoimmune disorder with progressive articular damage that may result in lifelong disability. Although major strides in understanding the disease have been made, the pathogenesis of RA has not yet been fully elucidated. Early treatment can prevent severe disability and lead to remarkable patient benefits, although a lack of therapeutic efficiency in a considerable number of patients remains problematic. MicroRNAs (miRNAs) are small, non-coding RNAs that, depending upon base pairing to messenger RNA (mRNA), mediate mRNA cleavage, translational repression or mRNA destabilization. As fine tuning regulators of gene expression, miRNAs are involved in crucial cellular processes and their dysregulation has been described in many cell types in different diseases. In body fluids, miRNAs are present in microvesicles or incorporated into complexes with Argonaute 2 (Ago2) or high-density lipoproteins and show high stability. Therefore, they are of interest as potential biomarkers of disease in daily diagnostic applications. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various animal models. Over the past several years it has become clear that alterations exist in the expression of miRNAs in patients with RA. Increasing numbers of studies have shown that dysregulation of miRNAs in peripheral blood mononuclear cells or isolated T lymphocytes, in synovial tissue and synovial fibroblasts that are considered key effector cells in joint destruction, contributes to inflammation, degradation of extracellular matrix and invasive behaviour of resident cells. Thereby, miRNAs maintain the pathophysiological process typical of RA. The aim of the current review is to discuss the available evidence linking the expression of miRNAs to inflammatory and immune response in RA and their potential as biomarkers and the novel targets for treatment in patients with RA.     

MicroRNA dysregulations in Merkel cell carcinoma: Molecular mechanisms and clinical applications

Merkel cell carcinoma (MCC) is an aggressive skin malignancy with two distinct etiologies. The first, which accounts for the highest proportion, is caused by Merkel cell polyomavirus (MCPyV), a DNA tumor virus. A second, UV-induced, MCC form has also been identified. Few MCC diagnostic, prognostic, and therapeutic options are available. MicroRNAs (miRNAs) are small noncoding RNA molecules, which play a key role in regulating various physiologic cellular functions including cell cycling, proliferation, differentiation, and apoptosis. Numerous miRNAs are dysregulated in cancer, by acting as either tumor suppressors or oncomiRs. The aim of this review is to collect, summarize, and discuss recent findings on miRNAs whose dysregulation has been assumed to play a role in MCC. The potential clinical application of miRNAs as diagnostic and prognostic biomarkers in MCC is also described. In the future, miRNAs will potentially gain clinical significance for the improvement of MCC diagnostic, prognostic, and therapeutic options.     

MicroRNAs in juvenile idiopathic arthritis: Can we learn more about pathophysiological mechanisms?

Juvenile idiopathic arthritis (JIA) is a heterogeneous and multifactorial group of chronic arthritis with an onset before the age of 16 years. The pathogenesis of this disease is poorly understood, which makes the distinction among subtypes unclear, delays diagnosis and optimal therapeutic management. MicroRNAs (miRNAs) are small non-coding RNAs that play a critical role in the regulation of immune responses. Their expression is tightly controlled to ensure cellular homeostasis and function of innate and adaptive immune cells. Abnormal expression of miRNAs has been associated with the development of many inflammatory and autoimmune diseases. In this review, we gather results published on miRNAs expression profiles in JIA patients with the aim to identify miRNAs that can be used as diagnostic biomarkers and provide information on disease activity and progression. We also focus on miRNAs deregulated in different forms of JIA to shed light on common pathways potentially involved in disease pathophysiology.     

Macrophage phenotypes in atherosclerosis

Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype.     

Cytokines in atherosclerosis: pathogenic and regulatory pathways

Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.     

Circulating microRNAs: novel biomarkers for cardiovascular diseases

MicroRNAs (miRNAs) are a novel class of small, non-coding, single-stranded RNAs that negatively regulate gene expression via translational inhibition or mRNA degradation followed by protein synthesis repression. Many miRNAs are expressed in a tissue- and/or cell-specific manner and their expression patterns are reflective of underlying patho-physiologic processes. miRNAs can be detected in serum or in plasma in a remarkably stable form, making them attractive biomarkers for human diseases. This review describes the progress of identifying circulating miRNAs as novel biomarkers for diverse cardiovascular diseases, including acute myocardial infarction, heart failure, coronary artery disease, diabetes, stroke, essential hypertension, and acute pulmonary embolism. In addition, the origin and function and the different strategies to identify circulating miRNAs as novel biomarkers for cardiovascular diseases are also discussed. Rarely has an opportunity arisen to advance such new biology for the diagnosis of cardiac diseases.     

Understanding the role of B cells in atherosclerosis: potential clinical implications

Atherosclerosis is a progressive inflammatory disease of the medium to large arteries that is the largest contributor to cardiovascular disease. B-cell subsets have been shown in animal models of atherosclerosis to have both atherogenic and atheroprotective properties. In this review, we highlight the research that developed our understanding of the role of B cells in atherosclerosis both in humans and mice. From this we discuss the potential clinical impact B cells could have both as diagnostic biomarkers and as targets for immunotherapy. Finally, we recognize the inherent difficulty in translating findings from animal models into humans given the differences in both cardiovascular disease and the immune system between mice and humans, making the case for greater efforts at addressing the role of B cells in human atherosclerosis.     

Targeting leukocyte integrins in human diseases

As our understanding of integrins as multifunctional adhesion and signaling molecules has grown, so has their recognition as potential therapeutic targets in human diseases. Leukocyte integrins are of particular interest in this regard, as they are key molecules in immune-mediated and inflammatory processes and are thus critically involved in diverse clinical disorders, ranging from asthma to atherosclerosis. Antagonists that interfere with integrin-dependent leukocyte trafficking and/or post-trafficking events have shown efficacy in multiple preclinical models, but these have not always predicted success in subsequent clinical trials (e.g., ischemia-reperfusion disorders and transplantation). However, recent successes of integrin antagonists in psoriasis, inflammatory bowel disease, and multiple sclerosis demonstrate the tremendous potential of antiadhesion therapy directed at leukocyte integrins. This article will review the role of the leukocyte integrins in the inflammatory process, approaches to targeting leukocyte integrins and their ligands, and the results of completed clinical trials.     

Atherosclerosis in diabetes mellitus: role of inflammation

Inflammation plays a central role in the pathophysiology of atherosclerosis, starting from initiation, through progression and ultimately the thrombotic complications of atherosclerosis. Diabetes mellitus is a major risk factor for atherosclerosis. Hyperglycemia-induced endothelial dysfunctions, along with hypercoagulable potential of diabetes mellitus, accelerate the process of atherothrombotic complications. Therefore, clinically feasible markers to monitor subtle systemic inflammatory burden and specific add-on therapy for the same constitute need of the present day. The understanding of the concept of inflammation in diabetes-accelerated atherosclerosis can be used practically to predict future cardiovascular risk by evaluating inflammatory biomarkers and to design clinical trials making inflammation as a therapeutic target.