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.
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