mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts.
mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts.
复制标题
DOI：
10.1161/circresaha.112.300658
复制
发表时间：
2013-06-07
影响因子：
20.1
通讯作者：
Wang DZ
中科院分区：
文献类型：
--
作者：
Chen J;Huang ZP;Seok HY;Ding J;Kataoka M;Zhang Z;Hu X;Wang G;Lin Z;Wang S;Pu WT;Liao R;Wang DZ
成年哺乳动物心脏中的心肌细胞是终末分化的细胞，已经退出细胞周期，失去了大部分的增殖能力。成熟心肌细胞在病理性心脏疾病中的死亡和成人心脏再生能力的缺乏是心力衰竭和死亡的主要原因。然而，出生后和成人心脏中的心肌细胞增殖如何受到抑制仍在很大程度上尚不清楚。MiR-17-92簇最初被确定为促进细胞增殖的人类癌基因。然而，它在心脏中的作用仍不清楚。验证miR-17-92参与调节出生后和成年心脏心肌细胞增殖的假说。我们从胚胎和出生后的小鼠心脏中删除了miR-17-92簇，并证明了miR-17-92是心肌细胞增殖所必需的。转基因miR-17-92在心肌细胞中的过表达足以诱导胚胎、出生后和成年心脏的心肌细胞增殖。此外，在成年心肌细胞中过表达miR-17-92可以保护心脏免受心肌梗死所致的损伤。同样，我们发现miR-17-92簇的成员，特别是miR-19，是体外诱导心肌细胞增殖所必需的，并且足以诱导心肌细胞的增殖。我们将抑癌基因PTEN确定为miR-17-92靶点，以介导miR-17-92在心肌细胞增殖中的作用。因此，我们的研究确定miR-17-92是心肌细胞增殖的关键调节因子，并建议该miRNAs簇可能成为心脏修复和心脏再生的治疗靶点。
Cardiomyocytes in adult mammalian hearts are terminally differentiated cells that have exited from the cell cycle and lost most of their proliferative capacity. Death of mature cardiomyocytes in pathological cardiac conditions and the lack of regeneration capacity of adult hearts are primary causes of heart failure and mortality. However, how cardiomyocyte proliferation in postnatal and adult hearts becomes suppressed remains largely unknown. The miR-17-92 cluster was initially identified as a human oncogene that promotes cell proliferation. However, its role in the heart remains unknown. To test the hypothesis that miR-17-92 participates in the regulation of cardiomyocyte proliferation in postnatal and adult hearts. We deleted miR-17-92 cluster from embryonic and postnatal mouse hearts and we demonstrated that miR-17-92 is required for cardiomyocyte proliferation in the heart. Transgenic overexpression of miR-17-92 in cardiomyocytes is sufficient to induce cardiomyocyte proliferation in embryonic, postnatal and adult hearts. Moreover, overexpression of miR-17-92 in adult cardiomyocytes protects the heart from myocardial infarction-induced injury. Similarly, we found that members of miR-17-92 cluster, miR-19 in particular, are required for and sufficient to induce cardiomyocyte proliferation in vitro. We identified PTEN, a tumor suppressor, as a miR-17-92 target to mediate the function of miR-17-92 in cardiomyocyte proliferation. Our studies therefore identify miR-17-92 as a critical regulator of cardiomyocyte proliferation and suggest this cluster of miRNAs could become therapeutic targets for cardiac repair and heart regeneration.