RESUMEN
BACKGROUND: The induction of cardiomyocyte (CM) proliferation is a promising approach for cardiac regeneration following myocardial injury. MicroRNAs (miRNAs) have been reported to regulate CM proliferation. In particular, miR-431 expression decreases during cardiac development, according to Gene Expression Omnibus (GEO) microarray data. However, whether miR-431 regulates CM proliferation has not been thoroughly investigated. METHODS: We used integrated bioinformatics analysis of GEO datasets to identify the most significantly differentially expressed miRNAs. Real-time quantitative PCR and fluorescence in situ hybridization were performed to determine the miRNA expression patterns in hearts. Gain- and loss-of-function assays were conducted to detect the role of miRNA in CM proliferation. Additionally, we detected whether miR-431 affected CM proliferation in a myocardial infarction model. The TargetScan, miRDB and miRWalk online databases were used to predict the potential target genes of miRNAs. Luciferase reporter assays were used to study miRNA interactions with the targeting mRNA. RESULTS: First, we found a significant reduction in miR-431 levels during cardiac development. Then, by overexpression and inhibition of miR-431, we demonstrated that miR-431 promotes CM proliferation in vitro and in vivo, as determined by immunofluorescence assays of 5-ethynyl-2'-deoxyuridine (EdU), pH3, Aurora B and CM count, whereas miR-431 inhibition suppresses CM proliferation. Then, we found that miR-431 improved cardiac function post-myocardial infarction. In addition, we identified FBXO32 as a direct target gene of miR-431, with FBXO32 mRNA and protein expression being suppressed by miR-431. FBXO32 inhibited CM proliferation. Overexpression of FBXO32 blocks the enhanced effect of miR-431 on CM proliferation, suggesting that FBXO32 is a functional target of miR-431 during CM proliferation. CONCLUSION: In summary, miR-431 promotes CM proliferation by targeting FBXO32, providing a potential molecular target for preventing myocardial injury.
Asunto(s)
MicroARNs , Proteínas Musculares , Infarto del Miocardio , Miocitos Cardíacos , Proteínas Ligasas SKP Cullina F-box , Proliferación Celular/genética , Hibridación Fluorescente in Situ , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Musculares/genética , Infarto del Miocardio/genética , Miocitos Cardíacos/citología , ARN Mensajero/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , AnimalesRESUMEN
There exist some fuzziness and uncertainty in the process of ecological construction. The aim of this paper is to develop a direct and an effective simplified method for obtaining the cost-sharing scheme when some interested parties form a cooperative coalition to improve the ecological environment of Min River together. Firstly, we propose the solution concept of the least square prenucleolus of cooperative games with coalition values expressed by trapezoidal intuitionistic fuzzy numbers. Then, based on the square of the distance in the numerical value between two trapezoidal intuitionistic fuzzy numbers, we establish a corresponding quadratic programming model to obtain the least square prenucleolus, which can effectively avoid the information distortion and uncertainty enlargement brought about by the subtraction of trapezoidal intuitionistic fuzzy numbers. Finally, we give a numerical example about the cost-sharing of ecological construction in Fujian Province in China to show the validity, applicability, and advantages of the proposed model and method.
