MicroRNA-1 downregulation increases connexin 43 displacement and induces ventricular tachyarrhythmias in rodent hypertrophic hearts.
MicroRNA-1 downregulation increases connexin 43 displacement and induces ventricular tachyarrhythmias in rodent hypertrophic hearts.
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DOI：
10.1371/journal.pone.0070158
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Indolfi C
中科院分区：
文献类型：
--
作者：
Curcio A;Torella D;Iaconetti C;Pasceri E;Sabatino J;Sorrentino S;Giampà S;Micieli M;Polimeni A;Henning BJ;Leone A;Catalucci D;Ellison GM;Condorelli G;Indolfi C
肌特异性microRNA-1(miR-1)的下调介导了病理性心肌肥厚的诱导。在心肌肥厚过程中，作为miR-1靶点的缝隙连接蛋白43(Cx43)功能障碍会导致室性快速性心律失常(VT)。然而，目前尚不清楚miR-1和Cx43是否在促心律失常的肥厚背景下相互联系。因此，在这项研究中，我们研究了心肌肥厚程度的减少是否可以通过调节miR-1水平来限制Cx43的病理性电重构和室性心动过速的发生。Wistar雄性大鼠机械收缩升主动脉造成病理性左心室肥厚(LVH)后，随机分成两组，分别给予10 mg/kg的Valsartan，Val(LVH+Val)或安慰剂(LVH)灌胃12周。对照组施行假手术。与LVH+Val组相比，LVH组可重复性地诱发室性心动过速。与假手术对照组相比，左心室肥厚组大鼠心肌miR-1表达显著降低，Cx43蛋白表达及ERK1/2依赖的磷酸化水平显著增加，使Cx43从缝隙连接中移位。有趣的是，给主动脉缩窄的大鼠服用Val可显著减少心肌肥厚，并防止miR-1下调和Cx43上调和磷酸化。体外培养的新生心肌细胞(NCMS)的功能获得和丧失实验证实，Cx43是miR-1的直接靶点。因此，与未刺激的NCMS相比，体外血管紧张素II刺激降低了miR-1水平，增加了Cx43表达和磷酸化。最后，在体内，通过心肌内注射腺病毒载体的miR-1心脏过表达减少了异丙肾上腺素诱导的左心室肥厚小鼠Cx43的表达和磷酸化。综上所述，miR-1在体内外调控肥大心肌细胞Cx43的表达和活性。治疗压力超负荷引起的心肌细胞肥大，通过使miR-1的表达水平正常化，从而稳定缝隙连接内的Cx43的表达和活性，从而降低危及生命的室速的风险。
Downregulation of the muscle-specific microRNA-1 (miR-1) mediates the induction of pathologic cardiac hypertrophy. Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT). However, it is still unknown whether miR-1 and Cx43 are interconnected in the pro-arrhythmic context of hypertrophy. Thus, in this study we investigated whether a reduction in the extent of cardiac hypertrophy could limit the pathological electrical remodeling of Cx43 and the onset of VT by modulating miR-1 levels. Wistar male rats underwent mechanical constriction of the ascending aorta to induce pathologic left ventricular hypertrophy (LVH) and afterwards were randomly assigned to receive 10mg/kg valsartan, VAL (LVH+VAL) delivered in the drinking water or placebo (LVH) for 12 weeks. Sham surgery was performed for control groups. Programmed ventricular stimulation reproducibly induced VT in LVH compared to LVH+VAL group. When compared to sham controls, rats from LVH group showed a significant decrease of miR-1 and an increase of Cx43 expression and its ERK1/2-dependent phosphorylation, which displaces Cx43 from the gap junction. Interestingly, VAL administration to rats with aortic banding significantly reduced cardiac hypertrophy and prevented miR-1 down-regulation and Cx43 up-regulation and phosphorylation. Gain- and loss-of-function experiments in neonatal cardiomyocytes (NCMs) in vitro confirmed that Cx43 is a direct target of miR-1. Accordingly, in vitro angiotensin II stimulation reduced miR-1 levels and increased Cx43 expression and phosphorylation compared to un-stimulated NCMs. Finally, in vivo miR-1 cardiac overexpression by an adenoviral vector intra-myocardial injection reduced Cx43 expression and phosphorylation in mice with isoproterenol-induced LVH. In conclusion, miR-1 regulates Cx43 expression and activity in hypertrophic cardiomyocytes in vitro and in vivo. Treatment of pressure overload-induced myocyte hypertrophy reduces the risk of life-threatening VT by normalizing miR-1 expression levels with the consequent stabilization of Cx43 expression and activity within the gap junction.
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影响因子：
5.5
作者：
Biagetti, Marcelo O.;Quinteiro, Ricardo A.
通讯作者：
Quinteiro, Ricardo A.
影响因子：
24
作者：
Ellison, Georgina M.;Torella, Daniele;Nadal-Ginard, Bernardo
通讯作者：
Nadal-Ginard, Bernardo
影响因子：
5
作者：
Emdad, L;Uzzaman, M;Murata, Y
通讯作者：
Murata, Y
影响因子：
11.2
作者：
Fedele, M;Fidanza, V;Fusco, A
通讯作者：
Fusco, A
DOI：
10.1074/jbc.m607391200
发表时间：
2007-04-13
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Ellison GM;Torella D;Karakikes I;Purushothaman S;Curcio A;Gasparri C;Indolfi C;Cable NT;Goldspink DF;Nadal-Ginard B
通讯作者：
Nadal-Ginard B