O2 SENSING BY MITOCHONDRIA DURING INTERMITTENT HYPOXIA

阻塞性睡眠呼吸暂停(OSA)是一种以反复发作为特征的临床综合征 间歇性上颌骨闭合引起的严重低氧血症 睡眠时的呼吸道。阻塞性睡眠呼吸暂停的并发症包括肺动脉高压 由肺内血管重塑引起。反复间歇性缺氧是 最有可能是这次改建的原因。重塑对低氧的反应 这意味着细胞氧气传感器的存在能够对快速反应 [O2]的变化。该实验室的研究表明，线粒体 在不同的细胞中，在低氧期间充当氧传感器，释放活性物质 氧物种(ROS)进入细胞质，触发细胞内信号转导 导致转录因子核因子激活的途径 Kappa B(NFkB)和低氧诱导因子(HIF-1)在某些细胞中的表达，以及 调节其他人的适应性代谢反应。此应用程序建议 线粒体在间歇性低氧中也起到氧气传感器的作用，通过 释放导致转录因子NFkB激活的ROS， 调节长期血管相关基因的HIF-I和AP-I 改建。生长因子有助于细胞的增殖。 血管壁，低氧通过一种未知的方式放大它们的有丝分裂反应 机制。缺氧时释放的线粒体ROS可放大 氧化信号增强对生长因子的促有丝分裂反应 它们的增殖反应所必需的。Aim我会决定是否 线粒体在间歇过程中释放ROS，起到氧气感受器的作用 缺氧。目标2将确定这些RO是否必要和充分 激活转录因子NFkB、HIF-I和AP-1，以及 这些因素是否介导了随后的转录激活 参与血管重塑的靶基因。目标3将决定是否 间歇性低氧通过以下途径增强对有丝分裂原的增殖反应 刺激线粒体ROS的产生，增强生长因子诱导的 非线粒体氧化剂信号转导。总的来说，这些研究可以 确定一种新的肺内氧气感知机制，并提供一种 基因转导和细胞激活的机制解释 间歇性低氧时细胞增殖。

Obstructive sleep apnea (OSA) is a clinical syndrome characterized by repeated episodes of severe hypoxemia caused by intermittent closure of the upper airway during sleep. Complications of OSA include pulmonary hypertension caused by vascular remodeling in the lung. Repeated intermittent hypoxia is the most likely cause of this remodeling. The remodeling responses to hypoxia imply that a cellular O2 sensor exists that is capable of responding to rapid changes in [O2]. Studies from this laboratory indicate that mitochondria function as O2 sensors during hypoxia in diverse cells, releasing reactive oxygen species (ROS) to the cytoplasm that trigger intracellular signaling pathways leading to the activation of the transcription factors Nuclear Factor kappa B (NFkB) and Hypoxia-Inducible Factor (HIF- 1) in some cells, and that mediate adaptive metabolic responses in others. This application proposes that mitochondria also function as O2 sensors during intermittent hypoxia, by releasing ROS that lead to the activation of the transcription factors NFkB, HIF- I and AP- I that regulate genes involved in long-term vascular remodeling. Growth factors contribute to proliferation of cells in the vascular wall, and hypoxia amplifies their mitogenic response via an unknown mechanism. Mitochondrial ROS released during hypoxia could amplify the mitogenic response to growth factors by augmenting the oxidant signaling required for their proliferative response. Aim I will determine whether mitochondria function as O2 sensors by releasing ROS during intermittent hypoxia. Aim 2 will determine whether these ROS are necessary and sufficient for the activation of the transcription factors NFkB, HIF- I and AP- 1, and whether these factors mediate the subsequent transcriptional activation of target genes involved in vascular remodeling. Aim 3 will determine whether intermittent hypoxia amplifies the proliferative response to mitogens by stimulating mitochondrial ROS generation that augments growth factor-induced non-mitochondrial oxidant signaling. Collectively, these studies could identify a novel mechanism of O2 sensing in the lung, and provide a mechanistic explanation for the activation of gene transcritpion and cellular proliferation during intermittent hypoxia.