Hypoxia-activated apoptosis of cardiac myocytes requires reoxygenation or a pH shift and is independent of p53.
Hypoxia-activated apoptosis of cardiac myocytes requires reoxygenation or a pH shift and is independent of p53.
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DOI：
10.1172/jci5871
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发表时间：
1999-08
期刊：
影响因子：
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通讯作者：
K. Webster;D. J. Discher;Shari Kaiser;O. Hernandez;B. Sato;N. Bishopric
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文献类型：
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作者：
K. Webster;D. J. Discher;Shari Kaiser;O. Hernandez;B. Sato;N. Bishopric
心肌缺血再灌注可引起心肌细胞凋亡，这可能是缺血性心脏病发生发展的重要特征。缺血和再灌注对细胞凋亡信号转导的相对贡献尚未确定。我们在这里报告，严重的慢性缺氧单独不会导致心肌细胞的细胞凋亡的文化。当快速收缩的心肌细胞暴露于慢性缺氧时，只有当细胞外pH值（[pH]（o））降低时才发生凋亡。当[pH]（o）被中和时，不发生细胞凋亡。缺氧培养的酸性培养基或外源性乳酸的加入刺激需氧心肌细胞的凋亡。缺氧-酸中毒介导的细胞死亡是独立的p53：在野生型和p53基因敲除小鼠分离的心肌细胞中发生了等效的凋亡，缺氧导致p53丰度或p53依赖性转录没有可检测到的变化。缺氧心肌细胞的复氧诱导25-30%的细胞凋亡，并且根据相同的标准也不依赖于p53。最后，同等水平的细胞凋亡，所示的DNA片段，诱导缺血再灌注，但不是单独的缺血，Langendorff灌注的野生型和p53基因敲除小鼠的心脏。我们得出的结论是，酸中毒、复氧和再灌注（而不是单独的缺氧（或缺血））是程序性细胞死亡的强烈刺激，而程序性细胞死亡基本上不依赖于p53。
Ischemia and reperfusion activate cardiac myocyte apoptosis, which may be an important feature in the progression of ischemic heart disease. The relative contributions of ischemia and reperfusion to apoptotic signal transduction have not been established. We report here that severe chronic hypoxia alone does not cause apoptosis of cardiac myocytes in culture. When rapidly contracting cardiac myocytes were exposed to chronic hypoxia, apoptosis occurred only when there was a decrease in extracellular pH ([pH](o)). Apoptosis did not occur when [pH](o) was neutralized. Addition of acidic medium from hypoxic cultures or exogenous lactic acid stimulated apoptosis in aerobic myocytes. Hypoxia-acidosis-mediated cell death was independent of p53: equivalent apoptosis occurred in cardiac myocytes isolated from wild-type and p53 knockout mice, and hypoxia caused no detectable change in p53 abundance or p53-dependent transcription. Reoxygenation of hypoxic cardiac myocytes induced apoptosis in 25-30% of the cells and was also independent of p53 by the same criteria. Finally, equivalent levels of apoptosis, as demonstrated by DNA fragmentation, were induced by ischemia-reperfusion, but not by ischemia alone, of Langendorff-perfused hearts from wild-type and p53 knockout mice. We conclude that acidosis, reoxygenation, and reperfusion, but not hypoxia (or ischemia) alone, are strong stimuli for programmed cell death that is substantially independent of p53.