CARDIOCYTE RESPONSES TO HYPOXIA

提出了一种慢性缺血/缺氧模型系统，用于力学研究 哺乳动物心脏细胞培养的失败和随后的适应。 已经建立了限制供氧的条件，最初 导致心肌细胞机械性衰竭，但过度暴露 启动一种恢复收缩能力的适应性反应。时间进程 心肌细胞对低氧的这种双相反应有5到7个 几天。初步数据表明，这种低氧介导的循环是 伴随着转录活性的一些戏剧性变化 某些基因，特别是那些涉及生物能量途径和 氧运输蛋白肌红蛋白。其他的初步研究已经 提示低氧调节细胞内的显著减少 环状AM-P，这不仅对分子有直接贡献 而且对心肌细胞的收缩反应也有遗传反应 慢性缺氧。“拟议研究的长期目标之一是 将这些和其他代谢和分子遗传变化与 低氧收缩抑制/适应循环，并决定是否 这些参数之间存在因果关系。自.以来 某些糖酵解酶基因似乎在低氧中被过度诱导 对这种诱导的机制进行了研究。 以及对调控信号的分析，这些信号允许这些基因 在心肌细胞中做出如此剧烈的反应。精确的分子机制 对缺血/缺氧所致的心肌细胞收缩衰竭 还不知道呢。提出了本文所述的体外模型 提供了一些独特的优势，不仅可以研究收缩故障 以及心肌细胞如何适应并最终克服 低氧应激。因为缺氧似乎是最主要的侮辱 从而导致缺血心脏的死亡，预计这些 研究将导致对主体的更准确的理解 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.