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Xiaobin Luo,
Zhenwei Pan,
Hongli Shan,
Jiening Xiao,
Xuelin Sun,
Ning Wang,
Huixian Lin,
Ling Xiao,
Ange Maguy,
Xiao-Yan Qi, [......],
Yong Zhang,
Yunlong Bai,
Jing Ai,
Lihua Sun,
Hang Lu,
Xiao-Yan Luo, Zhiguo Wang,
Yanjie Lu,
Baofeng Yang,
Stanley Nattel
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ABSTRACT: Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (IK1) is believed to be an important regulator of reentrant-spiral dynamics and a major component of AF-related electrical remodeling. MicroRNA-26 (miR-26) is predicted to target the gene encoding KIR2.1, KCNJ2. We found that miR-26 was downregulated in atrial samples from AF animals and patients and this downregulation was accompanied by upregulation of IK1/KIR2.1 protein. miR-26 overexpression suppressed expression of KCNJ2/KIR2.1. In contrast, miR-26 knockdown, inhibition, or binding-site mutation enhanced KCNJ2/KIR2.1 expression, establishing KCNJ2 as a miR-26 target. Knockdown of endogenous miR-26 promoted AF in mice, whereas adenovirus-mediated expression of miR-26 reduced AF vulnerability. Kcnj2-specific miR-masks eliminated miR-26-mediated reductions in Kcnj2, abolishing miR-26's protective effects, while coinjection of a Kcnj2-specific miR-mimic prevented miR-26 knockdown-associated AF in mice. Nuclear factor of activated T cells (NFAT), a known actor in AF-associated remodeling, was found to negatively regulate miR-26 transcription. Our results demonstrate that miR-26 controls the expression of KCNJ2 and suggest that this downregulation may promote AF.
The Journal of clinical investigation 04/2013; · 15.39 Impact Factor
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Journal of Cellular Physiology 01/2012; 227(2):877. · 3.87 Impact Factor
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Journal of Cellular Physiology 01/2012; 227(2):877. · 3.87 Impact Factor
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Journal of Cellular Physiology 01/2012; 227(2):877. · 3.87 Impact Factor
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Journal of Cell Science 09/2011; 124(Pt 18):3187. · 6.11 Impact Factor
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Journal of Biological Chemistry 08/2011; 286(32):28656. · 4.77 Impact Factor
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Journal of Biological Chemistry 08/2011; 286(32):28656. · 4.77 Impact Factor
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ABSTRACT: In the detection of optical radiation, the detecting accuracy is affected by optic power distribution of the detector's surface to a large extent. In addition, in the image-forming system, the quality of the image is greatly determined by the uniformity of the image's illumination distribution. However, in the practical optical system, affected by the factors such as field of view, false light and off axis and so on, the distribution of the image's illumination tends to be non uniform, so it is necessary to discuss the image plane's illumination in image-forming systems. In order to analyze the characteristics of the image-forming system at a full range, on the basis of photometry, the formulas to calculate the illumination of the imaging plane have been summarized by the numbers. Moreover, the relationship between the horizontal offset of the light source and the illumination of the image has been discussed in detail. After that, the influence of some key factors such as aperture angle, off-axis distance and horizontal offset on illumination of the image has been brought forward. Through numerical simulation, various theoretical curves of those key factors have been given. The results of the numerical simulation show that it is recommended to aggrandize the diameter of the exit pupil to increase the illumination of the image. The angle of view plays a negative role in the illumination distribution of the image, that is, the uniformity of the illumination distribution can be enhanced by compressing the angle of view. Lastly, it is proved that telecentric optical design is an effective way to advance the uniformity of the illumination distribution.
Journal of Physics Conference Series 03/2011; 276(1):012118.
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ABSTRACT: In cancers with wild-type (WT) p53 status, the function of p53 is inhibited through direct interaction with Mdm2 oncoprotein, a negative feedback loop to limit the function of p53. In response to cellular stress, p53 escapes the p53:Mdm2 negative feedback to accumulate rapidly to induce cell cycle arrest and apoptosis. We demonstrate herein that an microRNA miR-605 is a new component in the p53 gene network, being transcriptionally activated by p53 and post-transcriptionally repressing Mdm2. Activation of p53 upregulated miR-605 via interacting with the promoter region of the gene. Overexpression of miR-605 directly decreased Mdm2 expression at the post-transcriptional level but indirectly increased the transcriptional activity of p53 on miR-34a via downregulating Mdm2; knockdown of miR-605 did the opposite. Mdm2 inhibitor upregulated expression of both miR-34a and miR-605, which was mitigated by p53 inhibitor. miR-605 preferentially induced apoptosis in WT p53-expressing cells, an effect abolished by p53 inhibition. These results indicate that miR-605 acts to interrupt p53:Mdm2 interaction to create a positive feedback loop aiding rapid accumulation of p53 to facilitate its function in response to stress.
The EMBO Journal 02/2011; 30(3):524-32. · 9.20 Impact Factor
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PLoS ONE 01/2011; 6(11). · 4.09 Impact Factor
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The EMBO Journal 01/2011; 30(24):5021. · 9.20 Impact Factor
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Baofeng Yang,
Huixian Lin,
Jiening Xiao,
Yanjie Lu,
Xiaobin Luo,
Baoxin Li,
Ying Zhang,
Chaoqian Xu,
Yunlong Bai,
Huizhen Wang,
Guohao Chen, Zhiguo Wang
Nature medicine 01/2011; 17(12):1693. · 27.14 Impact Factor
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Baofeng Yang,
Huixian Lin,
Jiening Xiao,
Yanjie Lu,
Xiaobin Luo,
Baoxin Li,
Ying Zhang,
Chaoqian Xu,
Yunlong Bai,
Huizhen Wang,
Guohao Chen, Zhiguo Wang
Nature medicine 01/2011; 17(12):1693. · 27.14 Impact Factor
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ABSTRACT: Abnormal QT prolongation is the major cardiac electrical disorder and a predictor of mortality in diabetic patients. Our previous studies suggest that dysfunction of delayed rectifier K(+) current (I(Kr)) is the main cause for the problem. Here we report the potential therapeutic role and mechanisms of vitamin E in the rabbit model of diabetes. The QT interval and action potential duration were considerably prolonged with frequent occurrence of ventricular tachyarrhythmias in diabetic rabbits. Administration of vitamin E corrected the abnormal QT prolongation and abolished the arrhythmic incidence. I(Kr) was found markedly reduced resulting in slowing of cardiac repolarization thereby QT prolongation in diabetic hearts. The diabetic depression of I(Kr) is primarily ascribed to oxidative damages to the cardiac membrane and proteins, as indicated by the overproduction of reactive oxygen species leading to severe lipid peroxidation and protein oxidation. Moreover, I(Kr) depression is most likely due to the dysfunction of HERG K(+) channel, the major subunit underlying native I(Kr), in response to oxidative stress, for peroxide anion-generating system produced similar depression of HERG channels. Vitamin E restored the depressed I(Kr) and HERG by its antioxidant actions which likely underlie its beneficial effects on diabetic QT prolongation and the associated arrhythmias. The data indicate that an antioxidant is sufficient for reversing the I(Kr)/I(HERG) dysfunction and the consequent electrical disorders in diabetic hearts. Our study also conceptually simplifies the complex nature of diabetic electrical disorders to primarily oxidative stress, and should stimulate interest in antioxidants as a therapeutic strategy for diabetic QT prolongation.
Cellular Physiology and Biochemistry 01/2011; 28(1):97-102. · 2.86 Impact Factor
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ABSTRACT: The human ether-à-go-go-1 (h-eag1) K(+) channel is expressed in a variety of cell lines derived from human malignant tumors and in clinical samples of several different cancers, but is otherwise absent in normal tissues. It was found to be necessary for cell cycle progression and tumorigenesis. Specific inhibition of h-eag1 expression leads to inhibition of tumor cell proliferation. We report here that h-eag1 expression is controlled by the p53-miR-34-E2F1 pathway through a negative feed-forward mechanism. We first established E2F1 as a transactivator of h-eag1 gene through characterizing its promoter region. We then revealed that miR-34, a known transcriptional target of p53, is an important negative regulator of h-eag1 through dual mechanisms by directly repressing h-eag1 at the post-transcriptional level and indirectly silencing h-eag1 at the transcriptional level via repressing E2F1. There is a strong inverse relationship between the expression levels of miR-34 and h-eag1 protein. H-eag1antisense antagonized the growth-stimulating effects and the upregulation of h-eag1 expression in SHSY5Y cells, induced by knockdown of miR-34, E2F1 overexpression, or inhibition of p53 activity. Therefore, p53 negatively regulates h-eag1 expression by a negative feed-forward mechanism through the p53-miR-34-E2F1 pathway. Inactivation of p53 activity, as is the case in many cancers, can thus cause oncogenic overexpression of h-eag1 by relieving the negative feed-forward regulation. These findings not only help us understand the molecular mechanisms for oncogenic overexpression of h-eag1 in tumorigenesis but also uncover the cell-cycle regulation through the p53-miR-34-E2F1-h-eag1 pathway. Moreover, these findings place h-eag1 in the p53-miR-34-E2F1-h-eag1 pathway with h-eag as a terminal effecter component and with miR-34 (and E2F1) as a linker between p53 and h-eag1. Our study therefore fills the gap between p53 pathway and its cellular function mediated by h-eag1.
PLoS ONE 01/2011; 6(5):e20362. · 4.09 Impact Factor
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Yanjie Lu,
Ying Zhang,
Ning Wang,
Zhenwei Pan,
Xu Gao,
Fengmin Zhang,
Yong Zhang,
Hongli Shan,
Xiaobin Luo,
Yunlong Bai,
Lihua Sun,
Wuqi Song,
Chaoqian Xu, Zhiguo Wang,
Baofeng Yang
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ABSTRACT: A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca(2+) current and shortening of the action potential duration. The possibility that microRNAs (miRNAs) may be involved in this process has not been tested. Accordingly, we assessed the potential role of miRNAs in regulating experimental AF.
The miRNA transcriptome was analyzed by microarray and verified by real-time reverse-transcription polymerase chain reaction with left atrial samples from dogs with AF established by right atrial tachypacing for 8 weeks and from human atrial samples from AF patients with rheumatic heart disease. miR-223, miR-328, and miR-664 were found to be upregulated by >2 fold, whereas miR-101, miR-320, and miR-499 were downregulated by at least 50%. In particular, miR-328 level was elevated by 3.9-fold in AF dogs and 3.5-fold in AF patients relative to non-AF subjects. Computational prediction identified CACNA1C and CACNB1, which encode cardiac L-type Ca(2+) channel α1c- and β1 subunits, respectively, as potential targets for miR-328. Forced expression of miR-328 through adenovirus infection in canine atrium and transgenic approach in mice recapitulated the phenotypes of AF, exemplified by enhanced AF vulnerability, diminished L-type Ca(2+) current, and shortened atrial action potential duration. Normalization of miR-328 level with antagomiR reversed the conditions, and genetic knockdown of endogenous miR-328 dampened AF vulnerability. CACNA1C and CACNB1 as the cognate target genes for miR-328 were confirmed by Western blot and luciferase activity assay showing the reciprocal relationship between the levels of miR-328 and L-type Ca(2+) channel protein subunits.
miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca(2+) channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF.
Circulation 12/2010; 122(23):2378-87. · 14.74 Impact Factor
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Zhiguo Wang
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ABSTRACT: Cardiomyocytes are excitable cells that can generate and propagate excitations; excitability is a fundamental characteristic of these cells, which is reflected by action potential; the changes of transmembrane potential as a function of time; and orchestrated by ion channels, transporters, and cellular proteins. The electrical excitation evoked in muscles must be transformed into mechanical contraction through the so-called excitation-contraction coupling mechanism, and the proper contraction of cardiac muscles then drives pumping of blood to the body circulation. Arrhythmias are electrical disturbances that can result in irregular heart beating with consequent insufficient pumping of blood. Arrhythmias are often lethal, constituting a major cause for cardiac death, particularly sudden cardiac death, in myocardial infarction and heart failure. Recent studies have led to discovery of microRNAs (miRNAs) as a new player in the cardiac excitability by fine-tuning expression of ion channels, transporters, and cellular proteins, which determines the arrhythmogenicity in many conditions. This review article will give a comprehensive summary on the data available in the literature. The basics of cardiac excitability will first be introduced, followed by a brief introduction to the basics of miRNAs. Then, studies on regulation of cardiac excitability by miRNAs will be described and analyzed. Finally, concluding remarks will be provided.
Journal of cardiovascular pharmacology 11/2010; 56(5):460-70. · 2.83 Impact Factor
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ABSTRACT: Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia associated with pronounced morbidity, mortality, and socio-economic burden. This pathological entity is associated with an altered expression profile of genes that are important for atrial function. MicroRNAs (miRNAs), a new class of non-coding mRNAs of around 22 nucleotides in length, have rapidly emerged as one of the key players in the gene expression regulatory network. The potential roles of miRNAs in controlling AF have recently been investigated. The studies have provided some promising results for our better understanding of the molecular mechanisms of AF. In this review article, we provide a synopsis of the studies linking miRNAs to cardiac excitability and other processes pertinent to AF. To introduce the main topic, we discuss basic knowledge about miRNA biology and our current understanding of mechanisms for AF. The most up-to-date research data on the possible roles of miRNAs in AF initiation and maintenance are presented, and the available experimental results on miRNA and AF are discussed. Some speculations pertinent to the subject are made. Finally, perspectives on future directions of research on miRNAs in AF are provided.
Cardiovascular research 11/2010; 89(4):710-21. · 5.80 Impact Factor
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Zhiguo Wang
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ABSTRACT: Progressive cell loss due to apoptosis is a pathological hallmark implicated in a wide spectrum of degenerative diseases such as heart disease, atherosclerotic arteries and hypertensive vessels, Alzheimer's disease and other neurodegenerative disorders. Tremendous efforts have been made to improve our understanding of the molecular mechanisms and signaling pathways involved in apoptosistic cell death. Once ignored completely or overlooked as cellular detritus, microRNAs (miRNAs) that were discovered only a decade ago, have recently taken many by surprise. The importance of miRNAs has steadily gained appreciation and miRNA biology has exploded into a massive swell of interest with enormous range and potential in almost every biological discipline because of their widespread expression and diverse functions in both animals and humans. It has been established that miRNAs are critical regulators of apoptosis of various cell types. These small molecules act by repressing the expression of either the proapoptotic or antiapoptotic genes to produce antiapoptotic or proapoptotic effects. Appealing evidence has been accumulating for the involvement of miRNAs in human diseases associated with apoptotic cell death and the potential of miRNAs as novel therapeutic targets for the treatment of the diseases. This editorial aims to convey this message and to boost up the research interest by providing a timely, comprehensive overview on regulation of apoptosis by miRNAs and a synopsis on the pathophysiologic implications of this novel regulatory network based on the currently available data in the literature. It begins with a brief introduction to apoptosis and miRNAs, followed by the description of the fundamental aspects of miRNA biogenesis and action, and the role of miRNAs in regulating apoptosis of cancer cells and cardiovascular cells. Speculations on the development of miRNAs as potential therapeutic targets are also presented. Remarks are also provided to point out the unanswered questions and to outline the new directions for the future research of the field.
World journal of biological chemistry. 04/2010; 1(4):41-54.
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ABSTRACT: Excitability is a fundamental characteristic of cardiac cells, which is delicately determined by ion channel activities modulated by many factors. MicroRNA (miRNA) expression is dynamically regulated and altered miRNA expression can render expression deregulation of ion channel genes leading to channelopathies-arrhythmogenesis. Indeed, evidence has emerged indicating the crucial role of miRNAs in controlling cardiac excitability by regulating expression of ion channel genes at the post-transcriptional level. However, the very limited experimental data in the literature hinder our understanding of the role of miRNAs and the often one-to-one interaction between miRNA and ion-channel gene in the published studies also casts a doubt about fullness of our view. Unfortunately, currently available techniques do not permit thorough characterization of miRNA targeting; computational prediction programs remain the only source for rapid identification of a putative miRNA target in silico. We conducted a rationally designed bioinformatics analysis in conjunction with experimental approaches to identify the miRNAs from the currently available miRNA databases which have the potential to regulate human cardiac ion channel genes and to validate the analysis with several pathological settings associated with the deregulated miRNAs and ion channel genes in the heart. We established a matrix of miRNAs that are expressed in cardiac cells and have the potential to regulate the genes encoding cardiac ion channels and transporters. We were able to explain a particular ionic remodeling process in hypertrophy/heart failure, myocardial ischemia, or atrial fibrillation with the corresponding deregulated miRNAs under that pathological condition; the changes of miRNAs appear to have anti-correlation with the changes of many of the genes encoding cardiac ion channels under these situations. These results indicate that multiple miRNAs might be critically involved in the electrical/ionic remodeling processes of cardiac diseases through altering their expression in cardiac cells, which has not been uncovered by previous experimental studies.
Cellular Physiology and Biochemistry 01/2010; 25(6):571-86. · 2.86 Impact Factor
