Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction.
Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction.
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DOI：
10.1161/circulationaha.111.044354
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发表时间：
2012-06-05
期刊：
影响因子：
37.8
通讯作者：
Rodriguez A
中科院分区：
文献类型：
--
作者：
Gurha P;Abreu-Goodger C;Wang T;Ramirez MO;Drumond AL;van Dongen S;Chen Y;Bartonicek N;Enright AJ;Lee B;Kelm RJ Jr;Reddy AK;Taffet GE;Bradley A;Wehrens XH;Entman ML;Rodriguez A
阐明microRNAs(MiRNAs)在转录后基因调控中的作用为心脏如何适应病理性应激提供了新的见解。我们在小鼠身上开发了miR-22的基因敲除，并研究了它在心脏中的功能。在这里，我们表明miR-22缺陷的小鼠对多巴酚丁胺的急性应激反应的变力和变力反应受损。此外，miR-22的缺失使小鼠在长期压力超负荷刺激后出现心脏失代偿和左心室扩张。钙瞬变分析显示突变心肌细胞肌浆网钙负荷降低与肌浆网钙ATPase活性抑制有关。基因切除miR-22还导致心脏SERCA2a和在心脏Z盘/titin细胞骨架附近编码蛋白质的肌肉限制性基因的表达水平下降。这些表型部分归因于应激心脏对血清反应因子活性的不适当抑制。全局分析显示，转录/翻译抑制物富嘌呤元件结合蛋白B的表达增加，这是一个高度保守的miR-22靶标，与肌肉表达的负调控有关。这些数据表明，miR-22在心脏应激期间作为钙离子稳态和肌原纤维蛋白含量的积分器发挥作用，并阐明了增加心力衰竭倾向的机制。
Delineating the role of microRNAs (miRNAs) in the posttranscriptional gene regulation offers new insights into how the heart adapts to pathological stress. We developed a knockout of miR-22 in mice and investigated its function in the heart. Here, we show that miR-22–deficient mice are impaired in inotropic and lusitropic response to acute stress by dobutamine. Furthermore, the absence of miR-22 sensitized mice to cardiac decompensation and left ventricular dilation after long-term stimulation by pressure overload. Calcium transient analysis revealed reduced sarcoplasmic reticulum Ca2+ load in association with repressed sarcoplasmic reticulum Ca2+ ATPase activity in mutant myocytes. Genetic ablation of miR-22 also led to a decrease in cardiac expression levels for Serca2a and muscle-restricted genes encoding proteins in the vicinity of the cardiac Z disk/titin cytoskeleton. These phenotypes were attributed in part to inappropriate repression of serum response factor activity in stressed hearts. Global analysis revealed increased expression of the transcriptional/translational repressor purine-rich element binding protein B, a highly conserved miR-22 target implicated in the negative control of muscle expression. These data indicate that miR-22 functions as an integrator of Ca2+ homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure.