Oh H, Taffet G E, Youker K A, Entman M L, Overbeek P A, Michael L H, Schneider M D
Center for Cardiovascular Development, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10308-13. doi: 10.1073/pnas.191169098. Epub 2001 Aug 21.
Cardiac muscle regeneration after injury is limited by "irreversible" cell cycle exit. Telomere shortening is one postulated basis for replicative senescence, via down-regulation of telomerase reverse transcriptase (TERT); telomere dysfunction also is associated with greater sensitivity to apoptosis. Forced expression of TERT in cardiac muscle in mice was sufficient to rescue telomerase activity and telomere length. Initially, the ventricle was hypercellular, with increased myocyte density and DNA synthesis. By 12 wk, cell cycling subsided; instead, cell enlargement (hypertrophy) was seen, without fibrosis or impaired function. Likewise, viral delivery of TERT was sufficient for hypertrophy in cultured cardiac myocytes. The TERT virus and transgene also conferred protection from apoptosis, in vitro and in vivo. Hyperplasia, hypertrophy, and survival all required active TERT and were not seen with a catalytically inactive mutation. Thus, TERT can delay cell cycle exit in cardiac muscle, induce hypertrophy in postmitotic cells, and promote cardiac myocyte survival.
损伤后心肌再生受“不可逆”细胞周期退出的限制。端粒缩短是复制性衰老的一种假定基础，通过下调端粒酶逆转录酶（TERT）实现；端粒功能障碍也与更高的细胞凋亡敏感性相关。在小鼠心肌中强制表达TERT足以挽救端粒酶活性和端粒长度。最初，心室细胞增多，心肌细胞密度增加且DNA合成增加。到12周时，细胞周期活动减弱；取而代之的是出现细胞增大（肥大），且无纤维化或功能受损。同样，通过病毒递送TERT足以使培养的心肌细胞肥大。TERT病毒和转基因在体外和体内也赋予了对细胞凋亡的保护作用。细胞增生、肥大和存活均需要有活性的TERT，而催化失活的突变则不会出现这些情况。因此，TERT可以延迟心肌细胞的细胞周期退出，诱导有丝分裂后细胞肥大，并促进心肌细胞存活。
