Endothelial dysfunction is an important predictor of cardiovascular risk, which is heightened in patients with obstructive sleep apnea (OSA). There is increasing evidence that conduit vessel endothelial dysfunction is associated with endothelial dysfunction in other vessels, including in the coronary vessels and in the microvasculature. We and others have shown that OSA patients have impaired endothelial function and increased endothelin. We propose to investigate the molecular mechanisms underlying endothelial dysfunction in OSA using a novel method of micro-vessel harvesting in humans. From these micro-vessels, we will analyze changes in endothelial cell membrane micro-domains called caveolae, which are the epicenter of signal transduction events, and are vital to maintaining endothelial homeostasis. Caveolae harbor multiple growth factor and G-coupled receptor complexes that regulate both nitric oxide and endothelin-1 synthesis, such that perturbations in these endothelial cell membrane micro-domains would determine the regional vasoactive profile. Caveolin-1, an integral protein of membrane caveolar micro-domains, negatively regulates endothelial nitric oxide synthase (eNOS) activity, and endothelial dysfunction in OSA is linked to decreased eNOS activity. Our preliminary in vitro data show that increased leptin and hypoxia, both of which are present in OSA patients, can each induce caveolin-1 expression, hence reducing eNOS and impairing endothelial function. Our additional data show that reactive oxygen species (ROS), also present in OSA patients, can disrupt caveolae by causing a biochemical shift in the protein milieu of these membrane micro-domains. We further provide in vivo evidence that endothelial caveolin-1 expression is increased in OSA patients. Since OSA is characterized by increased serum leptin, ROS and intermittent hypoxemia, we hypothesize that endothelial dysfunction associated with OSA is a result of molecular alterations within endothelial caveolar micro-domains. In this proposal we will study first, the in-vitro effects of leptin, ROS and intermittent hypoxia on caveolar micro-domains and subsequent eNOS and endothelin-1 activity (Specific Aim #1);and second, the morphological and biochemical changes in caveolar micro-domains in OSA patients compared to non-OSA patients (Specific Aim #2). We hypothesize that heightened levels of leptin, hypoxia and ROS in OSA induce increased endothelial cell caveolin-1 expression, resulting in decreased eNOS activity and increased endothelin-1 secretion, and that both of these are associated with impaired endothelial function, promoting a vasoconstrictor profile in OSA. The innovative strengths of our proposal lie in our ability to investigate the molecular mechanisms leading to endothelial dysfunction in OSA patients along with supporting in vitro experiments. Furthermore, the translational studies outlined in this proposal will provide pivotal molecular insights into the mechanisms surrounding endothelial dysfunction in OSA patients, which will enable a platform for development of novel therapeutic strategies directed at reversing endothelial dysfunction in OSA.

Public Health Relevance

This proposal will investigate the molecular mechanisms responsible for abnormal blood vessel function in patients with obstructive sleep apnea (OSA). The results of our studies may be helpful in the development of therapeutics for cardiovascular disease risks associated with OSA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065176-12
Application #
8607203
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Lathrop, David A
Project Start
1999-09-30
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
12
Fiscal Year
2014
Total Cost
$357,750
Indirect Cost
$132,750
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Konecny, Tomas; Khanna, Amber D; Novak, Jan et al. (2014) Interatrial pressure gradients during simulated obstructive sleep apnea: a catheter-based study. Catheter Cardiovasc Interv 84:1138-45
Shamsuzzaman, Abu; Amin, Raouf S; Calvin, Andrew D et al. (2014) Severity of obstructive sleep apnea is associated with elevated plasma fibrinogen in otherwise healthy patients. Sleep Breath 18:761-6
Konecny, Tomas; Kara, Tomas; Somers, Virend K (2014) Obstructive sleep apnea and hypertension: an update. Hypertension 63:203-9
Shamsuzzaman, Abu; Ackerman, Michael J; Kuniyoshi, Fatima Sert et al. (2014) Sympathetic nerve activity and simulated diving in healthy humans. Auton Neurosci 181:74-8
Calvin, Andrew D; Somers, Virend K; Johnson, Bruce D et al. (2014) Left atrial size, chemosensitivity, and central sleep apnea in heart failure. Chest 146:96-103
Ludka, Ondrej; Stepanova, Radka; Vyskocilova, Martina et al. (2014) Sleep apnea prevalence in acute myocardial infarction--the Sleep Apnea in Post-acute Myocardial Infarction Patients (SAPAMI) Study. Int J Cardiol 176:13-9
Mansukhani, Meghna P; Kara, Tomas; Caples, Sean M et al. (2014) Chemoreflexes, sleep apnea, and sympathetic dysregulation. Curr Hypertens Rep 16:476
Olson, Lyle J; Somers, Virend K (2013) Chemoreflexes, sympathetic excitation, and heart failure-challenges and opportunities. J Card Fail 19:416-8

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