CARDIOCYTE RESPONSES TO HYPOXIA

建立了慢性缺血/缺氧模型系统， 哺乳动物心脏细胞培养的失败和随后的适应。 已经建立了有限氧气供应的条件， 会导致心肌细胞的机械故障， 引起恢复收缩性适应性反应。的时间过程 心肌细胞对缺氧的这种双相反应的百分比为5 - 7 天初步数据表明，这种缺氧介导的循环是 伴随着转录活性的一些戏剧性的变化， 某些基因，特别是那些参与生物能量途径的基因， 氧转运蛋白肌红蛋白。额外的初步研究 表明缺氧介导细胞内 环AM-P，这可能不仅直接有助于分子 遗传反应，而且心脏细胞的收缩反应， 慢性缺氧拟议研究的一个长期目标是 将这些和其他代谢和分子遗传变化与 缺氧收缩抑制/适应循环，并确定是否 参数之间存在因果关系。以来 某些糖酵解酶基因似乎在低氧环境中被过度诱导， 心肌细胞的这种诱导机制的调查提出 沿着对调控信号的分析，这些信号允许这些基因 在心肌细胞中的反应如此剧烈。精确的分子机制 对于缺血/缺氧介导的心肌细胞收缩衰竭， 尚不清楚。建议此处描述的体外模型 提供了一些独特的优势，不仅可以研究收缩失败， 还包括心肌细胞如何适应并最终克服 低氧应激由于缺氧似乎是主要的损伤 导致缺血性心脏死亡，预计这些 研究将导致更准确地了解主要的 最终导致缺血性心力衰竭的分子事件。

A model system of chronic ischemia/hypoxia is proposed to study mechanical failure and subsequent adaptation of mammalian heart cell cultures. Conditions of limited oxygen supply have been established which initially cause mechanical failure of the cardiac myocyte but over extended exposures invoke an adaptive response which restores contractility. The time course of this biphasic response of the cardiocytes to hypoxia was five to seven days. Preliminary data has indicated that this hypoxia mediated cycle is accompanied by some dramatic changes in the transcriptional activity of certain genes in particular those involved in bioenergetic pathways and the oxygen transport protein myoglobin. Additional preliminary studies have suggested that hypoxia mediates significant reductions of intracellular cyclic AM-P and that this may contribute directly not only to the molecular genetic responses but also to contractile responses of the cardiocytes to chronic hypoxia. 'ne long term objectives of the proposed studies are to relate these and other metabolic and molecular genetic changes to the hypoxia contraction inhibition/adaptation cycle and to deter-mine whether there are cause and effect relationships between the parameters. Since certain glycolytic enzyme genes appear to be super-induced in the hypoxic cardiocytes an investigation of the mechanism of this induction is proposed along with analyses of regulatory signals which allow these genes to respond so dramatically in the cardiocyte. The precise molecular mechanism for ischemia/hypoxia mediated contractile failure of cardiac myocyte is sill not known. It is proposed that the in vitro model described here offers some unique advantages to investigate not only contractile failure but also how the cardiocytes can adapt to and ultimately overcome the hypoxic stress. Since oxygen deprivation appears to be the primary insult leading, to fatality in the ischemic heart it is anticipated that these studies will lead to a more precise understanding of the principal molecular events which culminate in ischemic heart failure.