Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure.
Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure.
复制标题
DOI：
10.1093/cvr/cvab210
复制
发表时间：
2022-06-22
影响因子：
10.8
通讯作者：
中科院分区：
文献类型：
--
作者：
Takotsubo综合征（TTS）是一种急性心力衰竭，通常由身体或情绪紧张时肾上腺素过高引发。它与心肌梗死（MI）的区别在于心室基底部过度收缩，心尖节段收缩减弱，并且没有罪魁祸首冠状动脉闭塞。我们的目的是了解最近发现的循环生物标志物miR-16和miR-26a是否在机制上参与了TTS的病理生理。miR-16和miR-26a可以区分TTS和MI。miR-16和miR-26a在肾上腺素丸诱导的AAV和TTS大鼠中共过表达。未处理的分离大鼠心肌细胞转染预/抗mir并进行功能评估。转染mir的动物在诱导TTS后，心室基底部过度收缩和心尖凹陷加重。体外miR-16和/或miR-26a过表达在分离的根尖（而不是基底）心肌细胞中产生强烈的收缩抑制，并失去肾上腺素敏感性。它们还增强了肾上腺素在基底细胞中的初始正性肌力作用。在未衰竭的人心肌细胞中重现了TTS-miRs后收缩力的下降。miR靶点的生物信息学分析，随后的表达分析和功能实验，确定了CACNB1 （l型钙通道Cavβ亚基），RGS4 （g蛋白信号传导4的调节剂）和g蛋白亚基Gβ (GNB1)的减少是这些作用的基础。miR-16和miR-26a使心脏对肾上腺素引起的tts样变化敏感。由于这些mir与焦虑和抑郁有关，它们可以提供一种机制，即由先前的压力引起的心脏启动导致未来TTS的可能性增加。
Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal), cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4), and G-protein subunit Gβ (GNB1) as underlying these effects. miR-16 and miR-26a sensitize the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future.
登录
查看更多内容
影响因子：
39.3
作者：
Ghadri JR;Wittstein IS;Prasad A;Sharkey S;Dote K;Akashi YJ;Cammann VL;Crea F;Galiuto L;Desmet W;Yoshida T;Manfredini R;Eitel I;Kosuge M;Nef HM;Deshmukh A;Lerman A;Bossone E;Citro R;Ueyama T;Corrado D;Kurisu S;Ruschitzka F;Winchester D;Lyon AR;Omerovic E;Bax JJ;Meimoun P;Tarantini G;Rihal C;Y-Hassan S;Migliore F;Horowitz JD;Shimokawa H;Lüscher TF;Templin C
通讯作者：
Templin C
影响因子：
5.1
作者：
Sato, M;O'Gara, P;Fuller, SJ
通讯作者：
Fuller, SJ
影响因子：
24
作者：
Ghadri, Jelena R.;Kato, Ken;Templin, Christian
通讯作者：
Templin, Christian
影响因子：
20.1
作者：
Pacak, Christina A.;Mah, Cathryn S.;Byrne, Barry J.
通讯作者：
Byrne, Barry J.
影响因子：
4.8
作者：
Liu, Ruijie;Ramani, Biswarathan;Xiang, Yang
通讯作者：
Xiang, Yang