P38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes
P38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes
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DOI：
10.1101/gad.1306705
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发表时间：
2005-05-15
影响因子：
10.5
通讯作者：
Keating, MT
中科院分区：
文献类型：
--
作者：
Engel, FB;Schebesta, M;Keating, MT
成年哺乳动物心肌细胞被认为是终末分化的，不能增殖。因此，急性损伤的哺乳动物心脏不会再生，它们会留下疤痕。在这里，我们表明，成年哺乳动物心肌细胞可以分裂。哺乳动物心肌细胞控制细胞周期的一个重要机制是p38 MAP激酶活性。p38调节心肌细胞中有丝分裂所需基因的表达，包括细胞周期蛋白A和细胞周期蛋白B。p38活性与发育过程中的心脏生长呈负相关，并且其过表达阻断胎儿心肌细胞增殖。MKK3bE在体内激活p38可使胎儿心肌细胞中BrdU掺入减少17.6%。相比之下，心脏特异性p38 α基因敲除小鼠显示新生心肌细胞有丝分裂增加92.3%。此外，在成年心肌细胞中抑制p38促进胞质分裂。最后，成年心肌细胞的有丝分裂与收缩器官的瞬时去分化有关。我们的研究结果表明p38是心肌细胞增殖的关键负调节因子，并表明成年心肌细胞可以分裂。
Adult mammalian cardiomyocytes are considered terminally differentiated and incapable of proliferation. Consequently, acutely injured mammalian hearts do not regenerate, they scar. Here, we show that adult mammalian cardiomyocytes can divide. One important mechanism used by mammalian cardiomyocytes to control cell cycle is p38 MAP kinase activity. p38 regulates expression of genes required for mitosis in cardiomyocytes, including cyclin A and cyclin B. p38 activity is inversely correlated with cardiac growth during development, and its overexpression blocks fetal cardiomyocyte proliferation. Activation of p38 in vivo by MKK3bE reduces BrdU incorporation in fetal cardiomyocytes by 17.6%. In contrast, cardiac-specific p38 alpha knockout mice show a 92.3% increase in neonatal cardiomyocyte mitoses. Furthermore, inhibition of p38 in adult cardiomyocytes promotes cytokinesis. Finally, mitosis in adult cardiomyocytes is associated with transient dedifferentiation of the contractile apparatus. Our findings establish p38 as a key negative regulator of cardiomyocyte proliferation and indicate that adult cardiomyocytes can divide.