Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling.
Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling.
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DOI：
10.1161/jaha.113.000078
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发表时间：
2013-04-23
影响因子：
5.4
通讯作者：
Lebeche D
中科院分区：
文献类型：
--
作者：
Karakikes I;Chaanine AH;Kang S;Mukete BN;Jeong D;Zhang S;Hajjar RJ;Lebeche D
microRNAs（miRNAs）在心力衰竭的发生发展中起着关键作用，最近的研究表明，肌肉特异性miR-1是心脏肥大的关键调节因子。我们检验了体内miR-1基因表达的慢性恢复将逆转肥大并防止压力超负荷诱导的不良心脏重塑的假设。在患有升主动脉瓣狭窄的雄性Sprague-道利大鼠中，通过左心室压力超负荷诱导心脏肥大。当在手术后2周建立肥大时，通过单次推注尾静脉注射将动物随机接受表达miR-1的腺相关病毒（AAV9.miR-1）或作为对照的绿色荧光蛋白（GFP）（AAV9.GFP）。miR-1的施用使心脏肥大消退（左室后壁厚度，; 2.32±0.08与2.75±0.07 mm，P<0.001），（左室间隔壁厚度，2.23±0.06与2.54±0.10 mm，P<0.05），并与对照治疗的动物相比停止了疾病进展，如通过超声心动图评估的治疗7周后的血流动力学分析（收缩末期压容积关系/有效动脉弹性，1.87±0.46 vs 0.96±0.38，P<0.05）。此外，miR-1替代治疗可显著减少心肌纤维化，改善钙处理，抑制细胞凋亡，并使丝裂原活化蛋白激酶信号通路失活，这表明对预防适应不良的心室重构具有有利作用。我们还鉴定并验证了miR-1的一种新型真正靶点Fibullin-2（Fbln 2），这是一种与细胞外基质重塑有关的分泌蛋白。总之，我们的研究结果表明，恢复miR-1基因表达是一种潜在的新的治疗策略，可以逆转压力诱导的心脏肥大并预防适应不良的心脏重塑。
MicroRNAs (miRNAs) play a key role in the development of heart failure, and recent studies have shown that the muscle‐specific miR‐1 is a key regulator of cardiac hypertrophy. We tested the hypothesis that chronic restoration of miR‐1 gene expression in vivo will regress hypertrophy and protect against adverse cardiac remodeling induced by pressure overload. Cardiac hypertrophy was induced by left ventricular pressure overload in male Sprague‐Dawley rats subjected to ascending aortic stenosis. When the hypertrophy was established at 2 weeks after surgery, the animals were randomized to receive either an adeno‐associated virus expressing miR‐1 (AAV9.miR‐1) or green fluorescent protein (GFP) as control (AAV9.GFP) via a single‐bolus tail‐vein injection. Administration of miR‐1 regressed cardiac hypertrophy (left ventricular posterior wall thickness,; 2.32±0.08 versus 2.75±0.07 mm, P<0.001) and (left ventricular septum wall thickness, 2.23±0.06 versus 2.54±0.10 mm, P<0.05) and halted the disease progression compared with control‐treated animals, as assessed by echocardiography (fractional shortening, 37.60±5.01% versus 70.68±2.93%, P<0.05) and hemodynamic analyses (end‐systolic pressure volume relationship/effective arterial elastance, 1.87±0.46 versus 0.96±0.38, P<0.05) after 7 weeks of treatment. Additionally, miR‐1 replacement therapy lead to a marked reduction of myocardial fibrosis, an improvement in calcium handling, inhibition of apoptosis, and inactivation of the mitogen‐activated protein kinase signaling pathways, suggesting a favorable effect on preventing the maladaptive ventricular remodeling. We also identified and validated a novel bona fide target of miR‐1, Fibullin‐2 (Fbln2), a secreted protein implicated in extracellular matrix remodeling. Taken together, our findings suggest that restoration of miR‐1 gene expression is a potential novel therapeutic strategy to reverse pressure‐induced cardiac hypertrophy and prevent maladaptive cardiac remodeling.