Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function
Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function
复制标题
DOI：
10.1073/pnas.1206432109
复制
发表时间：
2012-10-23
影响因子：
11.1
通讯作者：
McMullen, Julie R.
中科院分区：
文献类型：
--
作者：
Bernardo, Bianca C.;Gao, Xiao-Ming;McMullen, Julie R.
microRNA在心脏病的背景下失调，并已成为有前途的治疗靶点。MicroRNA-34家族成员（miR-34 a，-34b和-34c）在心脏中响应压力而上调。在这项研究中，我们评估了使用s.c.-递送的种子靶向8-mer锁核酸（LNA）修饰的antimiR（LNA-antimiR-34）可以在具有预先存在的病理性心脏重塑和功能障碍的小鼠中提供治疗益处，所述病理性心脏重塑和功能障碍是由于心肌梗死（MI）或通过横向主动脉缩窄（TAC）的压力超负荷引起的。给予另外一组经受MI的小鼠LNA-antimiR-34 a（15-mer）以单独抑制miR-34 a，作为LNA-antimiR-34的比较。LNA-antimiR-34（8-mer）在两种心脏应激模型中有效地沉默所有三种miR-34家族成员，并减弱心脏重塑和心房扩大。相比之下，在MI模型中，单独用LNA-抗miR-34 a（15-mer）抑制miR-34 a没有提供益处。在压力超负荷的小鼠中，LNA-antimiR-34改善了收缩功能并减轻了肺充血，这与心脏纤维化减少、血管生成增加、Akt活性增加、心房利钠肽基因表达减少和肌浆网Ca 2 + ATP酶基因表达维持有关。LNA-antimiR-34处理的MI和TAC小鼠的改善结果伴随着几种直接miR-34靶点的上调，包括血管内皮生长因子、黏着斑蛋白、蛋白质O-岩藻糖基转移酶1、Notch 1和脑信号蛋白4 B。我们的研究结果提供了证据表明，沉默整个miR-34家族可以保护心脏免受病理性心脏重塑并改善功能。此外，这些数据强调了种子靶向8-mer LNA-抗miR在开发用于药理学抑制疾病相关miRNA种子家族的新治疗方法中的效用。
MicroRNAs are dysregulated in a setting of heart disease and have emerged as promising therapeutic targets. MicroRNA-34 family members (miR-34a, -34b, and -34c) are up-regulated in the heart in response to stress. In this study, we assessed whether inhibition of the miR-34 family using an s.c.-delivered seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiR (LNA-antimiR-34) can provide therapeutic benefit in mice with preexisting pathological cardiac remodeling and dysfunction due to myocardial infarction (MI) or pressure overload via transverse aortic constriction (TAC). An additional cohort of mice subjected to MI was given LNA-antimiR-34a (15-mer) to inhibit miR-34a alone as a comparison for LNA-antimiR-34. LNA-antimiR-34 (8-mer) efficiently silenced all three miR-34 family members in both cardiac stress models and attenuated cardiac remodeling and atrial enlargement. In contrast, inhibition of miR-34a alone with LNA-antimiR-34a (15-mer) provided no benefit in the MI model. In mice subjected to pressure overload, LNA-antimiR-34 improved systolic function and attenuated lung congestion, associated with reduced cardiac fibrosis, increased angiogenesis, increased Akt activity, decreased atrial natriuretic peptide gene expression, and maintenance of sarcoplasmic reticulum Ca2+ ATPase gene expression. Improved outcome in LNA-antimiR-34-treated MI and TAC mice was accompanied by up-regulation of several direct miR-34 targets, including vascular endothelial growth factors, vinculin, protein O-fucosyltranferase 1, Notch1, and semaphorin 4B. Our results provide evidence that silencing of the entire miR-34 family can protect the heart against pathological cardiac remodeling and improve function. Furthermore, these data underscore the utility of seed-targeting 8-mer LNA-antimiRs in the development of new therapeutic approaches for pharmacologic inhibition of disease-implicated miRNA seed families.