MicroRNA-34a Plays a Key Role in Cardiac Repair and Regeneration Following Myocardial Infarction.
MicroRNA-34a Plays a Key Role in Cardiac Repair and Regeneration Following Myocardial Infarction.
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DOI：
10.1161/circresaha.117.305962
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发表时间：
2015-08-14
影响因子：
20.1
通讯作者：
Liao R
中科院分区：
文献类型：
--
作者：
Yang Y;Cheng HW;Qiu Y;Dupee D;Noonan M;Lin YD;Fisch S;Unno K;Sereti KI;Liao R
作为对损伤的反应，啮齿动物的心脏在生命的早期就能够通过心肌细胞增殖而完全再生。然而，这种再生能力早在出生后一周就会减弱，并在成年后继续丧失。在生命早期决定损伤后心肌细胞增殖的机制尚不清楚。描述miR-34a（一种与年龄相关的生理调节因子）在新生儿和成年小鼠心脏继发于心肌梗死（MI）的心脏再生中的作用。通过冠状动脉结扎的实验性心肌梗死诱导新生儿和成人心脏损伤。成人心脏表现出明显的心脏结构和功能重塑，而新生儿心脏保持完全的再生能力和心肌细胞增殖，并在一周内恢复到正常水平。早在出生后一周，miR-34a的表达就增加了，并在整个生命周期中保持在高水平。有趣的是，心肌梗死后7天，miR-34a水平在成人心脏中进一步升高，而在新生儿心脏中没有。将miR-34a模拟物递送至新生儿心脏可抑制心肌细胞增殖和心肌梗死后的心脏恢复。相反，基于锁定核酸的抗miR-34a治疗减少心肌梗死后成人心脏miR-34a上调，并显著改善心肌梗死后重构。在分离的心肌细胞中，我们发现miR-34a通过调节其靶基因，包括Bcl2、Cyclin D1和Sirt1，直接调节细胞周期活性和死亡。miR-34a是新生儿心肌梗死后心脏修复和再生的关键调节因子。miR-34a的调节可能用于成人心肌的心脏修复。
In response to injury, the rodent heart is capable of virtually full regeneration via cardiomyocyte proliferation very early in life. This regenerative capacity, however, is diminished as early as one week post-natal and remains lost in adulthood. The mechanisms that dictate post injury cardiomyocyte proliferation early in life remain unclear. To delineate the role of miR-34a, a regulator of age-associated physiology, in regulating cardiac regeneration secondary to myocardial infarction (MI) in neonatal and adult mouse hearts. Cardiac injury was induced in neonatal and adult hearts through experimental MI via coronary ligation. Adult hearts demonstrated overt cardiac structural and functional remodeling, whereas neonatal hearts maintained full regenerative capacity and cardiomyocyte proliferation, and recovered to normal levels within one week time. As early as one week post-natal, miR-34a expression was found to have increased and was maintained at high levels throughout the lifespan. Intriguingly, seven days following MI, miR-34a levels further increased in the adult but not neonatal hearts. Delivery of a miR-34a mimic to neonatal hearts prohibited both cardiomyocyte proliferation and subsequent cardiac recovery post-MI. Conversely, locked nucleic acid-based anti-miR-34a treatment diminished post-MI miR-34a upregulation in adult hearts and significantly improved post-MI remodeling. In isolated cardiomyocytes, we found that miR-34a directly regulated cell cycle activity and death via modulation of its target genes, including Bcl2, Cyclin D1, and Sirt1. miR-34a is a critical regulator of cardiac repair and regeneration post-MI in neonatal hearts. Modulation of miR-34a may be harnessed for cardiac repair in adult myocardium.