Myocyte adaptation to chronic hypoxia and development of tolerance to subsequent acute severe hypoxia
Myocyte adaptation to chronic hypoxia and development of tolerance to subsequent acute severe hypoxia
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DOI：
10.1161/01.res.80.5.699
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发表时间：
1997-05-01
影响因子：
20.1
通讯作者：
Stern, MD
中科院分区：
文献类型：
--
作者：
Silverman, HS;Wei, SK;Stern, MD
在动物模型和人类中的研究表明，心肌可以适应慢性或间歇性长时间发作的冠状动脉灌注减少。在实验模型中难以实现部分流量减少的稳定维持;因此，体外细胞模型可用于建立适应机制。由于中度缺氧可能是低流量状态的重要组成部分，因此将分离的成年大鼠心肌细胞暴露于1%O-2 48小时以研究慢性缺氧适应。低氧培养并没有降低细胞活力相对于常氧对照，但提高葡萄糖利用和乳酸生产，这是符合厌氧代谢模式乳酸生产保持短暂增加恢复正常O-2张力后。肌细胞收缩性降低（视频边缘分析），缺氧细胞中细胞内Ca 2+瞬变（indo 1荧光）的幅度也降低。弛豫减慢，并伴随着缓慢衰减的Ca 2+瞬变。这些变化不是由于动作电位的改变。耐受随后的急性严重缺氧发生在1%O-2培养的细胞，表现为在严重缺氧和增强的心肌细胞在复氧形态恢复的时间延迟到完全ATP耗尽僵硬挛缩。后者在延长至僵直时间的数据标准化后仍可见，表明耐受性的多因素基础。在随后的急性严重缺氧之前的常氧暴露的干预期并没有导致耐受性丧失，而是增加了随后的ATP耗竭僵硬的延迟。细胞糖原保存在慢性缺氧暴露和恢复正常的O-2张力后增加。由于线粒体细胞色素在远低于1%O-2的水平下应被充分氧化，因此低氧适应可能由低亲和力O-2感应过程介导。因此，适应过程中发生：长时间的中度缺氧，提出平衡的肌细胞在一个更好的位置，以容忍即将发生的严重O-2剥夺。
Studies in animal models and humans suggest that myocardium may adapt to chronic or intermittent prolonged episodes of reduced coronary perfusion. Stable maintenance of partial flow reduction is difficult to achieve in experimental models; thus, in vitro cellular models may be useful for establishing the mechanisms of adaptation. Since moderate hypoxia is likely to be an important component of the low-flow state, isolated adult rat cardiac myocytes were exposed to 1% O-2 for 48 hours to study chronic hypoxic adaptation. Hypoxic culture did not reduce cell viability relative to normoxic controls but did enhance glucose utilization and lactate production, which is consistent with an anaerobic pattern of metabolism Lactate production remained transiently increased after restoration of normal O-2 tension. Myocyte contractility was reduced (video-edge analysis), as was the amplitude of the intracellular Ca2+ transient (indo 1 fluorescence) in hypoxic cells. Relaxation was slowed and was accompanied by a slowed decay of the Ca2+ transient. These changes were not due to alterations in the action potential. Tolerance to subsequent acute severe hypoxia occurred in cells cultured in 1% O-2 and was manifested as a delay in the time to full ATP-depletion rigor contracture during severe hypoxia and enhanced morphological recovery of myocytes at reoxygenation. The latter was still seen after normalization of the data for the prolonged time to rigor, suggesting a multifactorial basis for tolerance. An intervening period of normoxic exposure before subsequent acute severe hypoxia did not result in loss of tolerance but rather increased the delay to subsequent ATP depletion rigor. Cellular glycogen was preserved during chronic hypoxic exposure and increased after the restoration of normal O-2 tension. As mitochondrial cytochromes should be fully oxygenated at levels well below 1% O-2, hypoxic adaptation may be mediated by a low-affinity O-2-sensing process. Thus, adaptations that occur during: prolonged periods of moderate hypoxia are proposed to poise the myocyte in a better position to tolerate impending episodes of severe O-2 deprivation.