【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(xì)胞數(shù)目的改變。初始的心肌肥厚是對(duì)外源性促肥厚刺激的一種適應(yīng)性反應(yīng)。當(dāng)外界應(yīng)力持續(xù)作用時(shí),心肌肥厚逐漸轉(zhuǎn)變?yōu)榉沁m應(yīng)性的病理性肥厚。病理性肥厚過(guò)程伴隨著有害事件的發(fā)生,如胎兒基因表達(dá)的上調(diào)、心臟收縮蛋白表達(dá)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(yán)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(guān)鍵風(fēng)險(xiǎn)因素,與其發(fā)病率、死亡率的增加密切相關(guān)。 miRNAs是內(nèi)源性的小分子非編碼RNA,長(zhǎng)度約18-25個(gè)核苷酸。miRNAs通過(guò)在轉(zhuǎn)錄后水平調(diào)控基因表達(dá)的方式發(fā)揮生物學(xué)功能。miRNAs通過(guò)seed序列特異性識(shí)別并結(jié)合靶mRNA,從而抑制靶mRNA的翻譯或促進(jìn)其降解,最終抑制靶基因的表達(dá)。越來(lái)越多的證據(jù)顯示miRNAs在心肌肥厚的病理過(guò)程中發(fā)揮重要作用。多個(gè)miRNAs已被確認(rèn)為心肌肥厚診斷和預(yù)后的標(biāo)志物,有的甚至被認(rèn)為是治療心肌肥厚的潛在靶點(diǎn)。本研究旨在探討miR-21-3p在心肌肥厚中的作用及其機(jī)制。 方法和結(jié)果 本研究發(fā)現(xiàn),miR-21-3p在胸主動(dòng)脈縮窄術(shù)(TAC)和血管緊張素Ⅱ (Ang Ⅱ)誘導(dǎo)的心肌肥厚模型小鼠的心臟組織中表達(dá)降低。進(jìn)一步探討miR-21-3p對(duì)心肌肥厚的作用,我們使用rAAV-miR-21-3p干預(yù)小鼠。形態(tài)學(xué)、心臟超聲、血流動(dòng)力學(xué)和心肌肥厚標(biāo)記物的檢測(cè)結(jié)果顯示,過(guò)表達(dá)miR-21-3p明顯抑制TAC和AngⅡ誘導(dǎo)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(dá)；熒光素酶報(bào)告基因結(jié)果證明miR-21-3p能夠直接結(jié)合于HDAC8的3’UTR。進(jìn)一步實(shí)驗(yàn)發(fā)現(xiàn),HDAC8的回輸通過(guò)增強(qiáng)磷酸化Akt和磷酸化Gsk3β的表達(dá)減弱miR-21-3p對(duì)心肌肥厚的保護(hù)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(dǎo)的小鼠的心肌肥厚。miR-21-3p通過(guò)抑制HDAC8的表達(dá)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(yīng)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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