miR-21-3p通过靶向调控组蛋白去乙酰化酶-8缓解心肌肥厚的作用及机制研究

发布时间：2019-05-26 21:15

【摘要】：研究背景和目的 心肌肥厚是指心脏体积增大,但不伴有心肌细胞数目的改变。初始的心肌肥厚是对外源性促肥厚刺激的一种适应性反应。当外界应力持续作用时,心肌肥厚逐渐转变为非适应性的病理性肥厚。病理性肥厚过程伴随着有害事件的发生,如胎儿基因表达的上调、心脏收缩蛋白表达的抑制、血管周围和间质的纤维化和心功能的下降。心肌肥厚往往造成严重的病理性心脏疾病,包括心功能不全、心肌病等。持续性的心肌肥厚是发生心力衰竭的关键风险因素,与其发病率、死亡率的增加密切相关。 miRNAs是内源性的小分子非编码RNA,长度约18-25个核苷酸。miRNAs通过在转录后水平调控基因表达的方式发挥生物学功能。miRNAs通过seed序列特异性识别并结合靶mRNA,从而抑制靶mRNA的翻译或促进其降解,最终抑制靶基因的表达。越来越多的证据显示miRNAs在心肌肥厚的病理过程中发挥重要作用。多个miRNAs已被确认为心肌肥厚诊断和预后的标志物,有的甚至被认为是治疗心肌肥厚的潜在靶点。本研究旨在探讨miR-21-3p在心肌肥厚中的作用及其机制。 方法和结果 本研究发现,miR-21-3p在胸主动脉缩窄术(TAC)和血管紧张素Ⅱ (Ang Ⅱ)诱导的心肌肥厚模型小鼠的心脏组织中表达降低。进一步探讨miR-21-3p对心肌肥厚的作用,我们使用rAAV-miR-21-3p干预小鼠。形态学、心脏超声、血流动力学和心肌肥厚标记物的检测结果显示,过表达miR-21-3p明显抑制TAC和AngⅡ诱导的小鼠的心肌肥厚。此外,Western blots结果显示,miR-21-3p抑制组蛋白去乙酰化酶8(HDAC8)的蛋白表达；荧光素酶报告基因结果证明miR-21-3p能够直接结合于HDAC8的3’UTR。进一步实验发现,HDAC8的回输通过增强磷酸化Akt和磷酸化Gsk3β的表达减弱miR-21-3p对心肌肥厚的保护作用。 结论 我们的结果显示,miR-21-3p能够明显缓解TAC和AngⅡ诱导的小鼠的心肌肥厚。miR-21-3p通过抑制HDAC8的表达调控AKt/Gsk3β通路,从而抑制心肌肥厚。Akt/Gsk3β通路是的miR-21-3p/HDAC8通路调控心肌肥厚反应的介质。miR-21-3p的调控为心肌肥厚的治疗提供了新的方向。
[Abstract]:Background and objective Myocardial hypertrophy refers to the increase of cardiac volume without the change of the number of cardiomyocytes. Initial myocardial hypertrophy is an adaptive response to exogenous hypertrophic stimulation. When the external stress continues, myocardial hypertrophy gradually changes to non-adaptive pathological hypertrophy. Pathological hypertrophy is accompanied by harmful events, such as up-regulation of fetal gene expression, inhibition of cardiac contractile protein expression, fibrosis around blood vessels and stroma, and decrease of cardiac function. Cardiac hypertrophy often leads to serious pathological heart diseases, including cardiac insufficiency, cardiomyopathy and so on. Persistent myocardial hypertrophy is a key risk factor for heart failure, which is closely related to the increase in incidence and mortality. MiRNAs is an endogenous small molecule non-coding RNA, with a length of about 18 to 25 nucleotides. MiRNAs play a biological role by regulating gene expression at the post-transcriptional level. MiRNAs are specifically recognized by seed sequences and combined with target mRNA, In order to inhibit the translation of target mRNA or promote its degradation, and finally inhibit the expression of target genes. More and more evidence shows that miRNAs plays an important role in the pathological process of myocardial hypertrophy. Many miRNAs have been identified as markers of diagnosis and prognosis of myocardial hypertrophy, and some of them are even considered to be potential targets for the treatment of myocardial hypertrophy. The purpose of this study was to investigate the role and mechanism of miR-21-3p in myocardial hypertrophy. Methods and results the expression of miR-21-3p in cardiac tissue of mice with cardiac hypertrophy induced by thoracic aortic constriction (TAC) and angiotensin 鈪，

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