miR-199a/miR-214簇激活NF-kB通路参与心肌肥厚的机制研究

NF-kB通路激活参与心肌肥厚进程，微小RNA(miRNAs)在心肌肥厚中发挥重要作用，但miRNAs是否调控心肌中NF-kB激活，尚不明确。我们发现miR-199a/miR-214簇在小鼠心肌肥厚的动物模型和细胞模型中显著上调，miR-199a和miR-214能激活NF-kB并促使心肌细胞肥大。推测NF-kB上调miR-199a和miR-214表达,这两个miRNA抑制包括CYLD、NKIRAS2、PTEN、Apelin和SIRT1在内的相应靶基因表达，进而协同正反馈激活NF-kB通路,促进心肌细胞肥大。本项目拟利用小鼠TAC模型、敲低心肌miR-199a和miR-214表达小鼠、Ang-II诱导小鼠心肌细胞肥大模型，从整体-细胞-分子水平，阐明miR-199a和miR-214对心肌肥厚发生、NF-kB激活和相应靶基因表达的调控机制，为以miRNAs为靶点的心肌肥厚治疗研究提供科学依据。

Recent studies reveal that activation of NF-kB signaling participates in cardiac hypertrophy.MicroRNAs(miRNAs) play important roles in the development of cardiac hypertrophy, but whether miRNAs modulate NF-kB activation in cardiac hypertrophy is still unknown. Our previous studies showed that miR-199a/miR-214-cluster was up-regulated in the myocardium of a mouse model of pressure-overload hypertrophy induced by transverse aortic constriction (TAC) and a mouse model of hypertrophy by subcutaneous injection of phenylephrine(PE). MiR-199a/miR-214-cluster was also shown up-regulated in PE-stimulated rat cardiomyocytes and in Ang-II-stimulated mouse cardiomyocytes. Additionaly,we found that miR-199a and miR-214 can stimulate NF-kB activation and hypertrophic phenotype in mouse cardiomyocytes. We hypothesize that NF-kB regulates miR-199a and miR-214 expression in cardiomyocytes, miR-214 modulates CYLD, NKIRAS2 and PTEN expression, and both miR-199a and miR-214 modulate Apelin and SIRT1 expression, contributing to a positive feedback activation of NF-kB and the cardiac hypertrophy. The TAC-induced C57BL/6 mouse model of hypertrophy, the C57BL/6 mice with knock-down of miR-199a or miR-214 in the myocardium, and the cell model of Ang-II-induced hypertrophy will be used in the present project. We will study the effects of miR-199a and -214 on the expression of corresponding target genes, on the NF-kB activation and on the onset of cardiac hypertrophy at the whole organism,cultural vessel, cellular and molecular level, respectively. The present study is expected to elucidate the potential roles of miR-199a/miR-214-cluster in cardiac hypertrophy and provide scientific evidence and material for future research on miRNAs-based therapy for cardiac hypertrophy.