Obesity is reaching epidemic proportions in the United States, and is associated with significant cardiovascular morbidity and mortality, representing a major public health burden. More than 50% of obese people exhibit Sleep Apnea (SA), which is characterized by upper airway collapse during sleep leading to repetitive periods of Intermittent Hypoxia (IH) and fragmentation of normal sleep architecture. SA, and in particular the stimulus of IH, can lead to a range of abnormalities in signaling pathways that cause cardiovascular disease. The current proposal focuses on three key signaling pathways - nitric oxide (NO), leptin. and tumor necrosis factor a (TNFa) - that are common to both SA and obesity and can impact on cardiac function. The premise of the proposal is that the IH stimulus of SA causes cardiac stress resulting in the development of ventricular hypertrophy and altered cardiac contractility. Deficits in NO and leptin signaling and increased levels of TNFa that occur with both SA and obesity will act to exacerbate the hypertrophy and attenuate the compensatory increases in cardiac contractility. Thus, the overall hypothesis is that SA is a link between obesity and cardiovascular disease, and that defects in NO, leptin, and TNFa signaling provide a mechanism for such a link.
Three Specific Aims examine the effect of NO and leptin deficiency, and overexpression of cardiac TNFa levels on the cardiac responses to five weeks of IH.
In Specific Aim #1. it is hypothesized that cardiac contractility increases more in neuronal than the endothelial NOS isoforms in response to IH, whereas the degree of ventricular hypertrophy is the same between isoforms.
In Specific Aim #2. it is hypothesized that the absence of leptin will depress cardiac contractility and accentuate the degree of ventricular hypertrophy caused by IH.
In Specific Aim #3. it is hypothesized that a decrease in cardiac contractility and an increase in ventricular hypertrophy occurs through a cardiac specific effect of TNFa in response to IH. Our approach utilizes lean knockout and transgenic mice and complementary control studies using pharmacological interventions to examine, independent of the confounding effects of obesity, the changes in cardiac function that occur both at the level of the whole heart and the isolated myocyte in response to IH. These proposed studies will dissect mechanisms by which SA exacerbates morbidity and mortality in obesity-related cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Laposky, Aaron D
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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