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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL077785-01A2
Application #
7093956
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Twery, Michael
Project Start
2006-04-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
1
Fiscal Year
2006
Total Cost
$394,551
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Khoo, Michael C K; Chalacheva, Patjanaporn (2016) Model-Derived Markers of Autonomic Cardiovascular Dysfunction in Sleep-Disordered Breathing. Sleep Med Clin 11:489-501
Chalacheva, P; Thum, J; Yokoe, T et al. (2013) Development of autonomic dysfunction with intermittent hypoxia in a lean murine model. Respir Physiol Neurobiol 188:143-51
Kaczmarek, Elzbieta; Bakker, Jessie P; Clarke, Douglas N et al. (2013) Molecular biomarkers of vascular dysfunction in obstructive sleep apnea. PLoS One 8:e70559
Naghshin, Jahan; Rodriguez, Rosa H; Davis, Eric M et al. (2012) Chronic intermittent hypoxia exposure improves left ventricular contractility in transgenic mice with heart failure. J Appl Physiol (1985) 113:791-8
Witham, William; Yester, Keith; O'Donnell, Christopher P et al. (2012) Restoration of glucose metabolism in leptin-resistant mouse hearts after acute myocardial infarction through the activation of survival kinase pathways. J Mol Cell Cardiol 53:91-100
Rame, J Eduardo; Barouch, Lili A; Sack, Michael N et al. (2011) Caloric restriction in leptin deficiency does not correct myocardial steatosis: failure to normalize PPAR{alpha}/PGC1{alpha} and thermogenic glycerolipid/fatty acid cycling. Physiol Genomics 43:726-38
McGaffin, Kenneth R; Witham, William G; Yester, Keith A et al. (2011) Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice. Cardiovasc Res 89:60-71
Yang, Ronghua; Sikka, Gautam; Larson, Jill et al. (2011) Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia. Am J Physiol Heart Circ Physiol 300:H1467-76
Sikka, G; Yang, R; Reid, S et al. (2010) Leptin is essential in maintaining normal vascular compliance independent of body weight. Int J Obes (Lond) 34:203-6
Lee, Euhan J; Woodske, Matthew E; Zou, Baobo et al. (2009) Dynamic arterial blood gas analysis in conscious, unrestrained C57BL/6J mice during exposure to intermittent hypoxia. J Appl Physiol (1985) 107:290-4

Showing the most recent 10 out of 12 publications