TWEAK is a positive regulator of cardiomyocyte proliferation
TWEAK is a positive regulator of cardiomyocyte proliferation
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DOI：
10.1093/cvr/cvp360
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发表时间：
2010-03-01
影响因子：
10.8
通讯作者：
Engel, Felix B.
中科院分区：
文献类型：
--
作者：
Novoyatleva, Tatyana;Diehl, Florian;Engel, Felix B.
哺乳动物心肌细胞的增殖在出生后的第一周停止，防止心脏在损伤后再生。最近，一些研究表明，诱导心肌细胞增殖可用于再生哺乳动物心脏。因此，重要的是要确定新的因素，可以诱导心肌细胞的增殖。在这里，我们确定了TNF相关的弱诱导凋亡（TWEAK）对心肌细胞的影响，已知的细胞因子调节增殖在其他几种细胞type.Stimulation的新生大鼠心肌细胞与TWEAK导致DNA合成增加，增殖标志物细胞周期蛋白D2和Ki 67的表达增加，细胞周期抑制剂p27 KIP 1的下调。重要的是，TWEAK刺激还导致有丝分裂（H3 P）、胞质分裂（Aurora B）和心肌细胞数量增加。功能丧失实验显示，增殖的再诱导依赖于肿瘤坏死因子受体超家族成员12 A（FN 14）信号传导。下游信号传导通过激活细胞外信号调节激酶和磷脂酰肌醇3-激酶以及抑制糖原合成酶激酶-3 β介导。与新生心肌细胞相反，由于其受体FN 14的发育下调，TWEAK对成年大鼠心肌细胞没有影响。然而，腺病毒表达的FN 14能够有效诱导TWEAK刺激后的成年心肌细胞重新进入细胞周期。
Proliferation of mammalian cardiomyocytes stops during the first weeks after birth, preventing the heart from regenerating after injury. Recently, several studies have indicated that induction of cardiomyocyte proliferation can be utilized to regenerate the mammalian heart. Thus, it is important to identify novel factors that can induce proliferation of cardiomyocytes. Here, we determine the effect of TNF-related weak inducer of apoptosis (TWEAK) on cardiomyocytes, a cytokine known to regulate proliferation in several other cell types.Stimulation of neonatal rat cardiomyocytes with TWEAK resulted in increased DNA synthesis, increased expression of the proliferative markers Cyclin D2 and Ki67, and downregulation of the cell cycle inhibitor p27KIP1. Importantly, TWEAK stimulation resulted also in mitosis (H3P), cytokinesis (Aurora B), and increased cardiomyocyte numbers. Loss of function experiments revealed that re-induction of proliferation was dependent on tumour necrosis factor receptor superfamily member 12A (FN14) signalling. Downstream signalling was mediated through activation of extracellular signal-regulated kinases and phosphatidylinositol 3-kinase as well as inhibition of glycogen synthase kinase-3beta. In contrast to neonatal cardiomyocytes, TWEAK had no effect on adult rat cardiomyocytes due to developmental downregulation of its receptor FN14. However, adenoviral expression of FN14 enabled efficient induction of cell cycle re-entry in adult cardiomyocytes after TWEAK stimulation.Our data establish TWEAK as a positive regulator of cardiomyocyte proliferation.