ROS in Episodic Hypoxia-Induced Cardiovascular Dysfunct*

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DESCRIPTION (provided by applicant): Sleep apnea is a common breathing disorder that is frequently associated with neurological and cardiovascular complications. However, the molecular mechanisms resulting in the cardiovascular dysfunction in sleep apnea remain largely unknown. Chronic intermittent hypoxia (CIH) during sleep is a hallmark of human sleep apnea. Strong evidence suggests that sleep apnea can increase cardiovascular morbidity and mortality. The major objective of the current research application is to delineate the molecular mechanisms of enhanced reactive oxygen species (ROS) production that result in the neural-mediated cardiovascular dysfunction induced by CIH during sleep apnea. The working hypothesis of the current application is that the oscillations in oxygen concentration during CIH mimic the ischemia (hypoxia)/re-oxygenation process and therefore will increase cellular ROS generation. Enhanced ROS production by CIH is the early and cardinal event that will attenuate baroreflex sensitivity, induce cardiac axonal degeneration, and consequently contribute to the cardiovascular dysfunction. Conversely, increasing antioxidants or antioxidant enzymatic activity that effectively inhibits ROS-mediated oxidative stress initiation and propagation may reduce or prevent CIH-induced cardiovascular dysfunction. The following specific aims are proposed to test the hypothesis that increased ROS production/antioxidant enzyme expression can facilitate/prevent neural-mediated cardiovascular dysfunction by CIH. 1. To establish and characterize a mouse model of CIH-induced cardiovascular dysfunction mimicking human sleep apnea. Specifically, we will first define the magnitude of hypoxia, cycle frequency, and exposure duration required for induction of cardiovascular dysfunction, as evidenced by elevated blood pressure, attenuated baroreflex sensitivity, and reduced brain-heart connections. 2. To identify and analyze molecular events of enhanced ROS production induced by CIH on the cardiovascular dysfunction. Specifically, we will combine free radical chemistry, biochemistry and molecular biology techniques to identify specific ROS production (oxidative stress propagation) that potentially contributes to brainstem neuronal cell damage leading to the cardiovascular dysfunction in the mouse model and in cell culture systems. 3. To define the fundamental roles of enhanced ROS production/antioxidant enzyme expression in the contribution/prevention of cardiovascular dysfunction. Specifically, we will utilize transgenic and knockout mouse approaches to examine whether enhanced/decreased antioxidant enzyme expression will attenuate/facilitate the previously defined cardiovascular dysfunctions induced by CIH. Since sleep apnea is a significant risk factor for cardiovascular dysfunction and chronic intermittent hypoxia is the essential element of sleep apnea, analysis of the molecular processes of ROS-mediated cardiovascular dysfunction may contribute significantly to the development of effective therapeutic approaches to reduce the risks of cardiovascular diseases associated with sleep apnea.