Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure.
Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure.
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DOI：
10.1161/circulationaha.111.030932
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发表时间：
2011-10-04
期刊：
影响因子：
37.8
通讯作者：
van Rooij E
中科院分区：
文献类型：
--
作者：
Montgomery RL;Hullinger TG;Semus HM;Dickinson BA;Seto AG;Lynch JM;Stack C;Latimer PA;Olson EN;van Rooij E
心肌肥厚引起的舒张功能障碍是一种主要的临床综合征，但治疗选择很少。MicroRNA通过抑制靶mRNA的翻译或促进靶mRNA的降解而作为基因表达的负调节因子。以前，我们报道了心脏特异性miR-208 a的基因缺失可以防止病理性心脏重塑和Myh 7的上调，以响应压力超负荷。这种miRNA是否可能导致舒张功能障碍或其他形式的心脏病目前尚不清楚。在这里，我们表明，全身递送反义寡核苷酸诱导心脏中miR-208 a的有效和持续沉默。在Dahl高血压大鼠中，通过皮下递送antimiR-208 a治疗性抑制miR-208 a在高血压诱导的心力衰竭期间剂量依赖性地防止病理性肌球蛋白转换和心脏重塑，同时改善心脏功能、总体健康和存活。转录谱显示antimiR-208 a对心脏基因表达有显著影响;血浆分析显示antimiR-208 a治疗后循环miRNA水平发生显著变化。这些研究表明了基于阿昔替丁的治疗用于调节心脏miRNA的潜力，并验证了miR-208作为调节心脏疾病进展期间心脏功能和重塑的有效治疗靶点。
Diastolic dysfunction in response to hypertrophy is a major clinical syndrome with few therapeutic options. MicroRNAs act as negative regulators of gene expression by inhibiting translation or promoting degradation of target mRNAs. Previously, we reported that genetic deletion of the cardiac-specific miR-208a prevents pathological cardiac remodeling and upregulation of Myh7 in response to pressure overload. Whether this miRNA might contribute to diastolic dysfunction or other forms of heart disease is currently unknown. Here, we show that systemic delivery of an antisense oligonucleotide induces potent and sustained silencing of miR-208a in the heart. Therapeutic inhibition of miR-208a by subcutaneous delivery of antimiR-208a during hypertension-induced heart failure in Dahl hypertensive rats dose-dependently prevents pathological myosin switching and cardiac remodeling while improving cardiac function, overall health, and survival. Transcriptional profiling indicates that antimiR-208a evokes prominent effects on cardiac gene expression; plasma analysis indicates significant changes in circulating levels of miRNAs on antimiR-208a treatment. These studies indicate the potential of oligonucleotide-based therapies for modulating cardiac miRNAs and validate miR-208 as a potent therapeutic target for the modulation of cardiac function and remodeling during heart disease progression.