Inhibition of miR-15 protects against cardiac ischemic injury.
Inhibition of miR-15 protects against cardiac ischemic injury.
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DOI：
10.1161/circresaha.111.244442
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发表时间：
2012-01-06
影响因子：
20.1
通讯作者：
van Rooij E
中科院分区：
文献类型：
--
作者：
Hullinger TG;Montgomery RL;Seto AG;Dickinson BA;Semus HM;Lynch JM;Dalby CM;Robinson K;Stack C;Latimer PA;Hare JM;Olson EN;van Rooij E
心肌梗死(MI)是世界范围内主要的死亡原因。由于内源性心脏修复机制不足以进行有意义的组织再生，心肌梗死会导致心脏组织丢失和有害的重塑事件。MicroRNAs(MiRNAs)是一种小的、非编码的RNA，以序列依赖的方式调节基因的表达。我们以前的数据表明，miRNAs在应对心脏缺血性损伤时处于失调状态，并积极参与心肌梗死后的心脏重构。本研究旨在确定猪心肌组织中miRNAs是否在缺血损伤中调节失调，以及锁定核酸(LNA)修饰的抗miR化学药物是否可以靶向心脏表达的miRNAs，从而在治疗上抑制缺血损伤中的miR-15。我们的数据表明，miR-15家族，包括6个密切相关的miRNAs，在小鼠和猪的心脏缺血再灌注损伤中受到心肌梗死区域的调控。LNA修饰的化学药物可以在体外有效地沉默miR-15家族成员，并使心肌细胞抵抗低氧诱导的心肌细胞死亡。相应地，系统递送miR-15抗miRs呈剂量依赖性地抑制小鼠和猪心脏组织中的miR-15，而治疗性靶向miR-15在小鼠中减少梗塞范围和心脏重构，并增强心肌梗死后的心功能。在心脏病中使用LNA修饰的化学药物调节心脏miRNAs的基于寡核苷酸的治疗是有效的，并验证了miR-15作为一种潜在的治疗靶点在操纵心脏重构和缺血性损伤的功能方面是有效的。
Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI. This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury. Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI. Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.