The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response.
The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response.
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DOI：
10.1016/j.cell.2014.03.032
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发表时间：
2014-04-24
期刊：
影响因子：
64.5
通讯作者：
Sadek HA
中科院分区：
文献类型：
--
作者：
Puente BN;Kimura W;Muralidhar SA;Moon J;Amatruda JF;Phelps KL;Grinsfelder D;Rothermel BA;Chen R;Garcia JA;Santos CX;Thet S;Mori E;Kinter MT;Rindler PM;Zacchigna S;Mukherjee S;Chen DJ;Mahmoud AI;Giacca M;Rabinovitch PS;Aroumougame A;Shah AM;Szweda LI;Sadek HA
哺乳动物心脏在出生后的短时间内具有显著的再生能力，此后大多数心肌细胞永久退出细胞周期。我们试图确定导致心肌细胞周期停滞的主要出生后事件。我们假设，过渡到富氧出生后的环境是上游信号，导致细胞周期停滞的心肌细胞。在这里，我们表明，活性氧（ROS），氧化DNA损伤，DNA损伤反应（DDR）标记显着增加，在心脏在出生后的第一周。有趣的是，出生后低氧血症，ROS清除，或抑制DDR都延长了出生后心肌细胞的增殖窗口，而高氧血症和ROS发生器缩短了它。这些发现揭示了一个以前未被认识到的保护机制，介导心肌细胞细胞周期阻滞，以换取利用氧依赖性有氧代谢。减少心肌细胞依赖性氧化应激应该是基于心肌细胞增殖的治疗方法的重要组成部分。
The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary post-natal event that results in cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen rich postnatal environment is the upstream signal that results in cell cycle arrest of cardiomyocytes. Here we show that reactive oxygen species (ROS), oxidative DNA damage, and DNA damage response (DDR) markers significantly increase in the heart during the first postnatal week. Intriguingly, postnatal hypoxemia, ROS scavenging, or inhibition of DDR all prolong the postnatal proliferative window of cardiomyocytes, while hyperoxemia and ROS generators shorten it. These findings uncover a previously unrecognized protective mechanism that mediates cardiomyocyte cell cycle arrest in exchange for utilization of oxygen dependent aerobic metabolism. Reduction of mitochondrial-dependent oxidative stress should be important component of cardiomyocyte proliferation-based therapeutic approaches.
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