Background:MicroRNAs are small, noncoding RNAs that play a key role in gene expression. Accumulating evidence suggests that aberrant microRNA expression contributes to the heart failure (HF) phenotype; however, the underlying molecular mechanisms are not well understood. A better understanding of the mechanisms of action of microRNAs could potentially lead to targeted therapies that could halt the progression or even reverse HF.Methods and Results:We found that microRNA-152 (miR-152) expression was upregulated in the failing human heart and experimental animal models of HF. Transgenic mice with cardiomyocyte-specific miR-152 overexpression developed systolic dysfunction (mean difference, −38.74% [95% CI, −45.73% to −31.74%]; P<0.001) and dilated cardiomyopathy. At the cellular level, miR-152 overexpression perturbed mitochondrial ultrastructure and dysregulated key genes involved in cardiomyocyte metabolism and inflammation. Mechanistically, we identified Glrx5 (glutaredoxin 5), a critical regulator of mitochondrial iron homeostasis and iron-sulfur cluster synthesis, as a direct miR-152 target. Finally, a proof-of-concept of the therapeutic efficacy of targeting miR-152 in vivo was obtained by utilizing a locked nucleic acid–based inhibitor of miR-152 (LNA 152) in a murine model of HF subjected to transverse aortic constriction. We demonstrated that animals treated with LNA–152 (n=10) showed preservation of systolic function when compared with locked nucleic acid–control treated animals (n=9; mean difference, 18.25% [95% CI, 25.10% to 11.39%]; P<0.001).Conclusions:The upregulation of miR-152 expression in the failing myocardium contributes to HF pathophysiology. Preclinical evidence suggests that miR-152 inhibition preserves cardiac function in a model of pressure overload–induced HF. These findings offer new insights into the pathophysiology of HF and point to miR-152-Glrx5 axis as a potential novel therapeutic target.

中文翻译：

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MicroRNA-152的药理沉默可防止压力超负荷引起的心力衰竭。

背景：MicroRNA是小的非编码RNA，在基因表达中起关键作用。越来越多的证据表明异常的microRNA表达有助于心力衰竭（HF）表型。然而，潜在的分子机制尚不十分清楚。更好地了解microRNA的作用机制可能会导致靶向治疗，从而可能阻止HF的进展甚至逆转。方法和结果：我们发现在衰竭的人心脏中microRNA-152（miR-152）的表达上调。 HF的实验动物模型。具有心肌细胞特异性miR-152过表达的转基因小鼠出现收缩功能障碍（平均差异为-38.74％[95％CI，-45.73％至-31.74％]；P<0.001）和扩张型心肌病。在细胞水平上，miR-152过表达扰乱了线粒体的超微结构，并且使参与心肌细胞代谢和炎症的关键基因失调。从机制上讲，我们确定了线粒体铁稳态和铁硫簇合成的关键调节剂Glrx5（谷氨酸还原酶5）为直接的miR-152靶标。最后，通过在经过横向主动脉缩窄的HF鼠模型中利用基于锁定核酸的miR-152抑制剂（LNA 152）获得了在体内靶向miR-152的治疗效果的概念证明。我们证明，与锁定核酸对照治疗的动物相比，用LNA-152（n = 10）治疗的动物表现出了收缩功能的保留（n = 9；平均差异为18.25％[95％CI，25.10％至11.39％] ;P <0.001）。结论：心肌衰竭中miR-152表达的上调与HF病理生理有关。临床前证据表明，在压力超负荷引起的心衰模型中，miR-152抑制可保留心脏功能。这些发现为HF的病理生理学提供了新的见识，并指出miR-152-Glrx5轴是潜在的新型治疗靶标。