發(fā)布時間：2019-05-26 21:15

【摘要】：研究背景和目的 心肌肥厚是指心臟體積增大,但不伴有心肌細胞數(shù)目的改變。初始的心肌肥厚是對外源性促肥厚刺激的一種適應性反應。當外界應力持續(xù)作用時,心肌肥厚逐漸轉(zhuǎn)變?yōu)榉沁m應性的病理性肥厚。病理性肥厚過程伴隨著有害事件的發(fā)生,如胎兒基因表達的上調(diào)、心臟收縮蛋白表達的抑制、血管周圍和間質(zhì)的纖維化和心功能的下降。心肌肥厚往往造成嚴重的病理性心臟疾病,包括心功能不全、心肌病等。持續(xù)性的心肌肥厚是發(fā)生心力衰竭的關鍵風險因素,與其發(fā)病率、死亡率的增加密切相關。 miRNAs是內(nèi)源性的小分子非編碼RNA,長度約18-25個核苷酸。miRNAs通過在轉(zhuǎn)錄后水平調(diào)控基因表達的方式發(fā)揮生物學功能。miRNAs通過seed序列特異性識別并結(jié)合靶mRNA,從而抑制靶mRNA的翻譯或促進其降解,最終抑制靶基因的表達。越來越多的證據(jù)顯示miRNAs在心肌肥厚的病理過程中發(fā)揮重要作用。多個miRNAs已被確認為心肌肥厚診斷和預后的標志物,有的甚至被認為是治療心肌肥厚的潛在靶點。本研究旨在探討miR-21-3p在心肌肥厚中的作用及其機制。 方法和結(jié)果 本研究發(fā)現(xiàn),miR-21-3p在胸主動脈縮窄術(TAC)和血管緊張素Ⅱ (Ang Ⅱ)誘導的心肌肥厚模型小鼠的心臟組織中表達降低。進一步探討miR-21-3p對心肌肥厚的作用,我們使用rAAV-miR-21-3p干預小鼠。形態(tài)學、心臟超聲、血流動力學和心肌肥厚標記物的檢測結(jié)果顯示,過表達miR-21-3p明顯抑制TAC和AngⅡ誘導的小鼠的心肌肥厚。此外,Western blots結(jié)果顯示,miR-21-3p抑制組蛋白去乙�；�8(HDAC8)的蛋白表達；熒光素酶報告基因結(jié)果證明miR-21-3p能夠直接結(jié)合于HDAC8的3’UTR。進一步實驗發(fā)現(xiàn),HDAC8的回輸通過增強磷酸化Akt和磷酸化Gsk3β的表達減弱miR-21-3p對心肌肥厚的保護作用。 結(jié)論 我們的結(jié)果顯示,miR-21-3p能夠明顯緩解TAC和AngⅡ誘導的小鼠的心肌肥厚。miR-21-3p通過抑制HDAC8的表達調(diào)控AKt/Gsk3β通路,從而抑制心肌肥厚。Akt/Gsk3β通路是的miR-21-3p/HDAC8通路調(diào)控心肌肥厚反應的介質(zhì)。miR-21-3p的調(diào)控為心肌肥厚的治療提供了新的方向。
[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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