miRNAs在心律失常中的作用研究进展

心律失常是心脏疾病常见的病症之一,不仅引起心脏功能障碍还可引起心源性猝死。Micro RNAs(mi RNAs)是一类长度约22 nt的单链非编码RNA。MiRNAs广泛参与细胞增殖、凋亡、分化、氧化应激等病理生理过程。MiRNAs不仅与心肌梗死、心肌肥厚及心肌纤维化等疾病发生密切相关,更与多种心脏病理状态下心脏电重构和心律失常的发生密切相关。近年来越来越多的研究证实miR-1、miR-328、let-7、miR-26、miR-208a等在心律失常发生发展过程中发挥了重要作用,并有望成为心律失常预警、诊断和治疗的新靶点。在这里阐述了这些miRNAs在心房纤颤、室性心律失常及心肌纤维化发生中的作用及意义。     

MicroRNAs在系统性硬化症纤维化中的作用及机制

微RNA（microRNAs,miRNAs）是在基因编码中起负性调控作用的内源性短链非编码RNA（non-coding RNAs,ncRNAs）,是生理和病理过程中基因表达必不可少的转录后调控物。miRNAs占人类基因组的1%～2%,通过与各自的mRNA结合并抑制其翻译,调节大于50%的人类基因及60%的哺乳动物蛋白质编码基因。系统性硬化症（systemic sclerosis,SSc）的发病机制由复杂的miRNAs网络调控。这些miRNAs位于与SSc纤维化相关的基因组区域,通过参与调节重要的细胞信号通路,如TGF-β、Wnt/β-catenin、TLR-4、IL和PDGF-β等,在SSc纤维化过程中发挥作用。同时,还与细胞信号转导、基质修复与重塑、成纤维细胞凋亡、胶原蛋白质合成和细胞外基质（extracellular matrix,ECM）沉积等相关。充分了解miRNAs在SSc纤维化中的重要性,有助于为SSc的诊断提供新的生物标记,为治疗提供新策略。本文综述了miRNAs在SSc纤维化过程中参与调节的这些复杂细胞信号通路的作用及机制,以期为SSc诊断、严重程度判断、预后评估,以及寻求潜在治疗靶点提供新思路。     

小鼠外周血心肌特异性microRNAs 的变化与病毒性心肌炎 相关关系初探

目的:通过识别病毒性心肌炎小鼠和正常小鼠血浆中miR-1,miR-133,miR-206表达量的差异,分析外周血中心肌特异性microRNAs的变化与病毒性心肌炎相关关系,为探索miRNAs作为病毒性心肌炎诊断的生物标志物提供可行性的研究资料。方法:在小鼠病毒性心肌炎模型的基础上,采用荧光定量PCR方法,检测病毒性心肌炎急性期小鼠组和正常小鼠组血浆中相关miRNAs含量,并进行统计学分析。再于病毒注射后1d,3d,5d,7d,9d,11d,分别处死病毒小鼠,观察血浆miRNAs的动态变化规律。同时用Elisa检测心肌肌钙蛋白的变化,对目的 miRNAs与心肌肌钙蛋白进行相关性分析。结果:急性期时三种miRNAs血浆含量显著上调。病毒注射后3d开始上升明显,并持续保持在较高水平到7d,于9d时开始下降。发病期间,血浆miRNAs含量与心肌肌钙蛋白呈现良好的正相关性。结论:小鼠外周血中心肌特异性microRNAs在病毒性心肌炎发病过程中的呈现明显上调并与病程和相应指标存在相关关系,为miRNAs作为病毒性心肌炎诊断的生物标志物提供了重要线索。     

microRNAs与心血管疾病

microRNAs(miRNAs)是一类长21~25 nt的非编码内源性蛋白质的RNAs,它们在转录后水平调控基因的表达,包括细胞增殖、分化和凋亡等一系列生理进程,影响生物体的生长发育,并与多种疾病相关。随着研究人员对microRNAs参与疾病的发病机制的研究,可能为人类某些疾病的治疗开辟一条新的途径。该文总结miRNAs在调控心血管疾病发生作用方面的研究成果,并对miRNA与心肌肥厚、心肌纤维化、心肌梗死、高血压、心率失常等的关系进行综述和展望。     

脂肪因子对心肌纤维化作用的研究进展

心肌纤维化是指心肌组织中细胞外基质过量沉积,过度的心肌纤维化可导致心脏舒缩功能障碍,最终可能诱导心力衰竭的发生。脂肪因子(adipokine)主要来源于脂肪组织,对糖脂代谢、炎症反应、免疫应答和心血管功能具有重要的调节作用。近年来的研究发现,脂肪因子亦参与心肌纤维化的发生和发展过程,构成促纤维化和抑纤维化的复杂的调节网络,影响心血管疾病的发展和转归。本文着重对脂肪因子参与心肌纤维化的研究进展进行综述。     

肠道菌群及其代谢产物对心肌纤维化影响与治疗的研究进展

心肌纤维化是多种心血管疾病,如冠心病、心肌梗死和心力衰竭等的终末期表现和主要致病因素。研究发现,免疫和炎症过程在心肌纤维化的发病机制中起决定性作用。近年来,人们发现肠道微生物在心肌纤维化的发病机制和发展中起着至关重要的作用。肠道菌群的失调可导致微生物的代谢产物转移到血液循环中,如短链脂肪酸、脂多糖和氧化三甲胺等。这些代谢物直接或间接地诱导组织损伤免疫和激活全身炎症反应,进而影响心肌纤维化。如何改变肠道菌群来改善心肌纤维化已成为当前的研究重点,包括饮食干预、使用抗生素、补充益生菌和益生元,以及粪便微生物群移植等。本综述旨在回顾肠道菌群及其代谢产物与心肌纤维化的相互作用,介绍通过干预肠道菌群改善心肌纤维化的研究进展,为心肌纤维化的治疗提供新思路。     

microRNAs在大鼠急性心肌梗死过程的表达变化

目的研究分析microRNAs（miRNAs,miRs）在大鼠急性心肌梗死（acutemyocardialinfarction,AMI）心肌组织的梗死区与非梗死区的表达变化,为防治AMI提供基础数据。方法选择雄性sD大鼠为研究对象,建立结扎左冠状动脉造成的急性心肌梗死模型,取建模后6h的梗死区与非梗死区的心肌组织进行芯片检测．确定其中表达变化显著的miRNAs;最后进行定量逆转录聚合酶链反应（qRT—PCR）,定量分析梗死区与非梗死区心肌组织中miRNAs的表达。结果AMI大鼠心肌组织中,芯片筛选出在AMI前后发生显著波动的miRNAs,与非梗死区相比,梗死区心肌组织中有26个miRNAs表达发生了显著变化,其中19个miRNA表达下调,7个miRNA表达上调。结论在AMI后的心肌组织的梗死部位与非梗死部位miRNAs的表达是有显著差异的,这对AMI阶段心肌保护的救治具有重要意义。     

microRNA调控心肌纤维化研究进展

心肌纤维化(myocardial fibrosis)是指致病因素导致心肌细胞外基质(extracellular matrix,ECM)合成和降解失衡,促使细胞外基质异常增多和过度积聚的病理过程。近年研究发现,miRNA可通过调节成纤维细胞的增殖和转化、细胞因子的分泌和胶原代谢参与心肌纤维化的发病过程。本文就近年关于miRNA参与和调控心肌纤维化的发生过程的研究进展进行综述,为心肌纤维化疾病的诊断和治疗提供理论参考。     

miRNAs与脂蛋白酯酶

miRNAs是一类具有调控基因功能的非编码RNAs,它在细胞核中合成,可转运至细胞质,调控脂质代谢相关性疾病的发生发展。脂蛋白酯酶(lipoprotein lipase,LPL)作为甘油三酯水解的限速酶,由心肌、脂肪、骨骼肌、乳腺及巨噬细胞等实质细胞合成和分泌,在脂蛋白转运和脂质代谢过程中发挥重要作用。近期研究证实多种miRNAs,包括miR-29、miR-467b、miR-590、miR-27、miR-134和miR-186,可通过调控脂蛋白酯酶LPL的表达,进而影响脂质代谢。为了深入探讨miRNAs对LPL的影响,本文以miRNAs对LPL的调控作用进行综述,期望以miRNAs为靶点,为脂质代谢相关性疾病的防治提供治疗方案。     

扩张型心肌病并发心力衰竭患者中参与花生四烯酸代谢调控的异常表达microRNAs的鉴定（英文）

心力衰竭作为一种具有较高发病率和死亡率的临床综合征,正成为日益严重的公共卫生问题。扩张型心肌病是心力衰竭的一种主要诱因,但其分子机制还有很多未知。之前的研究发现花生四烯酸(arachidonic acid, AA)代谢紊乱可导致心力衰竭的发生。为了探究调控花生四烯酸代谢的microRNAs (miRNAs)在扩张型心肌病并发心力衰竭过程中的作用,我们利用两个公共数据集中的miRNAs测序数据,分析了由扩张型心肌病引发的心力衰竭患者心肌组织中的miRNAs表达情况。我们分别在上述数据集中鉴定到101个和88个具有明显表达变化的miRNAs。在这些miRNAs里,大约有1/3的miRNAs被预测可以靶向调控AA代谢通路相关的基因。我们也研究了已知单核苷酸多态性(single nucleotide polymorphisms, SNPs)在扩张型心肌病并发心力衰竭患者中差异表达的miRNAs序列中的分布,发现在种子区域或整个序列上具有较多SNPs的miRNAs。以上这些结果可为未来研究miRNAs在扩张型心肌病并发心力衰竭发病机理中的功能提供线索。     

miRNA在心肌梗死中的作用及其机制研究进展

急性心肌梗死（AMI）是最常见的心血管事件,具有高发病率和高死亡率,严重威胁人类生命健康。微小RNA（miRNA）通过调节心肌细胞炎症、纤维化、细胞自噬及新生血管形成的表型机制发挥功能。本综述探讨了心肌梗死后miRNA上调及下调的分子机制,以及miRNA对心肌梗死早期诊断中的价值。     

Cardiac matrix: A clue for future therapy

Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium myocyte (EM) coupling and contractility of cardiomyocytes. The matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by EM coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases.     

MicroRNA signatures associated with thioacetamide-induced liver fibrosis in mice

Multiple etiologies of liver injury are associated with fibrosis in which the key event is the activation of hepatic stellate cells (HSCs). Although microRNAs (miRNAs) are reportedly involved in fibrogenesis, the complete array of miRNA signatures associated with the disease has yet to be elucidated. Here, deep sequencing analysis revealed that compared to controls, 80 miRNAs were upregulated and 21 miRNAs were downregulated significantly in the thioacetamide (TAA)-induced mouse fibrotic liver. Interestingly, 58 of the upregulated miRNAs were localized to an oncogenic miRNA megacluster upregulated in liver cancer. Differential expression of some of the TAA-responsive miRNAs was confirmed, and their human orthologs were similarly deregulated in TGF-β1-activated HSCs. Moreover, a functional analysis of the experimentally validated high-confidence miRNA targets revealed significant enrichment for the GO terms and KEGG pathways involved in HSC activation and liver fibrogenesis. This is the first comprehensive report of miRNAs profiles during TAA-induced mouse liver fibrosis.     

特异性microRNAs在心血管系统中的功能研究进展

MicroRNAs(miRNAs)是经核糖核酸酶(Dicer)加工后的一类非编码小RNA分子。在真核生物中,miRNA具有组织特异性和时序性,只在特定的组织和特定的发育阶段表达,在细胞生长和发育过程中起多种作用。miRNAs在心脏发育、形态生成、血管生成、心肌凋亡等多个生理病理过程中发挥重要作用。最近有大量研究发现某些特异性的miRNA对心血管的发育和心血管疾病有一定的影响。如miRNA-126调控血管生成;miRNA-143和miRNA-145决定血管平滑肌(VSMC)的分化和增殖;miRNA-208对心肌肥厚的调节;miRNA-1和miRNA-133影响心肌的发育、形态发生、心肌凋亡、心肌肥厚等。     

Integrated analyses identify the involvement of microRNA-26a in epithelial–mesenchymal transition during idiopathic pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and highly lethal fibrotic lung disease with poor treatment and unknown etiology. Emerging evidence suggests that epithelial–mesenchymal transition (EMT) has an important role in repair and scar formation following epithelial injury during pulmonary fibrosis. Although some miRNAs have been shown to be dysregulated in the pathophysiological processes of IPF, limited studies have payed attention on the participation of miRNAs in EMT in lung fibrosis. In our study, we identified and constructed a regulation network of differentially expressed IPF miRNAs and EMT genes. Additionally, we found the downregulation of miR-26a in mice with experimental pulmonary fibrosis. Further studies showed that miR-26a regulated HMGA2, which is a key factor in the process of EMT and had the maximum number of regulating miRNAs in the regulation network. More importantly, inhibition of miR-26a resulted in lung epithelial cells transforming into myofibroblasts in vitro and in vivo, whereas forced expression of miR-26a alleviated TGF-β1- and BLM-induced EMT in A549 cells and in mice, respectively. Taken together, our study deciphered the essential role of miR-26a in the pathogenesis of EMT in pulmonary fibrosis, and suggests that miR-26a may be a potential therapeutic target for IPF.     

The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families

Background

Chronic hepatitis C (CH) can develop into liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Liver fibrosis and HCC development are strongly correlated, but there is no effective treatment against fibrosis because the critical mechanism of progression of liver fibrosis is not fully understood. microRNAs (miRNAs) are now essential to the molecular mechanisms of several biological processes. In order to clarify how the aberrant expression of miRNAs participates in development of the liver fibrosis, we analyzed the liver fibrosis in mouse liver fibrosis model and human clinical samples.

Methodology

In a CCL₄-induced mouse liver fibrosis model, we compared the miRNA expression profile from CCL₄ and olive oil administrated liver specimens on 4, 6, and 8 weeks. We also measured expression profiles of human miRNAs in the liver biopsy specimens from 105 CH type C patients without a history of anti-viral therapy.

Principle Findings

Eleven mouse miRNAs were significantly elevated in progressed liver fibrosis relative to control. By using a large amount of human material in CH analysis, we determined the miRNA expression pattern according to the grade of liver fibrosis. We detected several human miRNAs whose expression levels were correlated with the degree of progression of liver fibrosis. In both the mouse and human studies, the expression levels of miR-199a, 199a*, 200a, and 200b were positively and significantly correlated to the progressed liver fibrosis. The expression level of fibrosis related genes in hepatic stellate cells (HSC), were significantly increased by overexpression of these miRNAs.

Conclusion

Four miRNAs are tightly related to the grade of liver fibrosis in both human and mouse was shown. This information may uncover the critical mechanism of progression of liver fibrosis. miRNA expression profiling has potential for diagnostic and therapeutic applications.     

Identification of a microRNA signature in renal fibrosis: role of miR-21

Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.     

MiR-34a/miR-93 target c-Ski to modulate the proliferaton of rat cardiac fibroblasts and extracellular matrix deposition in vivo and in vitro

Cardiac fibrosis is associated with diverse heart diseases. In response to different pathological irritants, cardiac fibroblasts may be induced to proliferate and differentiate into cardiac myofibroblasts, thus contributing to cardiac fibrosis. TGF-β signaling is implicated in the development of heart failure through the induction of cardiac fibrosis. C-Ski, an inhibitory regulator of TGF-β signaling, has been reported to suppress TGF-β1-induced human cardiac fibroblasts' proliferation and ECM protein increase; however, the underlying molecular mechanism needs further investigation. In the present study, we demonstrated that c-Ski could ameliorate isoproterenol (ISO)-induced rat myocardial fibrosis model and TGF-β1-induced primary rat cardiac fibroblasts' proliferation, as well as extracellular matrix (ECM) deposition. The protein level of c-Ski was dramatically decreased in cardiac fibrosis and TGF-β1-stimulated primary rat cardiac fibroblasts. In recent decades, a family of small non-coding RNA, namely miRNAs, has been reported to regulate gene expression by interacting with diverse mRNAs and inducing either translational suppression or mRNA degradation. Herein, we selected miR-34a and miR-93 as candidate miRNAs that might target to regulate c-Ski expression. After confirming that miR-34a/miR-93 targeted c-Ski to inhibit its expression, we also revealed that miR-34a/miR-93 affected TGF-β1-induced fibroblasts' proliferation and ECM deposition through c-Ski. Taken together, we demonstrated a miR-34a/miR-93-c-Ski axis which modulates TGF-β1- and ISO-induced cardiac fibrosis in vitro and in vivo; targeting the inhibitory factors of c-Ski to rescue its expression may be a promising strategy for the treatment of cardiac fibrosis.