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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Lathrop, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Xie, Jiang; Covassin, Naima; Chahal, Anwar A et al. (2018) Effect of Adaptive Servo-Ventilation on Periodic Limb Movements in Sleep in Patients With Heart Failure. Am J Cardiol :
Singh, Prachi; Zhang, Yuebo; Sharma, Pragya et al. (2018) Statins decrease leptin expression in human white adipocytes. Physiol Rep 6:
Medina-Inojosa, Jose R; Batsis, John A; Supervia, Marta et al. (2018) Relation of Waist-Hip Ratio to Long-Term Cardiovascular Events in Patients With Coronary Artery Disease. Am J Cardiol 121:903-909
Covassin, Naima; Sert-Kuniyoshi, Fatima H; Singh, Prachi et al. (2018) Experimental Weight Gain Increases Ambulatory Blood Pressure in Healthy Subjects: Implications of Visceral Fat Accumulation. Mayo Clin Proc 93:618-626
Cundrle Jr, Ivan; Somers, Virend K; Singh, Prachi et al. (2018) Low leptin concentration may identify heart failure patients with central sleep apnea. J Sleep Res 27:240-243
Xie, Jiang; Sert Kuniyoshi, Fatima H; Covassin, Naima et al. (2018) Excessive Daytime Sleepiness Independently Predicts Increased Cardiovascular Risk After Myocardial Infarction. J Am Heart Assoc 7:
Chahal, Anwar A; Alhurani, Rabe E; Mohamed, Essa A et al. (2017) Are there sex differences following treatment of left ventricular outflow tract obstruction in adults with hypertrophic cardiomyopathy? Eur Heart J Qual Care Clin Outcomes 3:249-250
Watanabe, Eiichi; Kiyono, Ken; Matsui, Shojiro et al. (2017) Prognostic Importance of Novel Oxygen Desaturation Metrics in Patients With Heart Failure and Central Sleep Apnea. J Card Fail 23:131-137
Polonis, Katarzyna; Somers, Virend K; Becari, Christiane et al. (2017) Moderate-to-severe obstructive sleep apnea is associated with telomere lengthening. Am J Physiol Heart Circ Physiol 313:H1022-H1030
Wang, Ling; Chen, Jiyan; Li, Guangxi et al. (2017) The Prevalence of Sleep Apnea in Type B Aortic Dissection: Implications for False Lumen Thrombosis. Sleep 40:

Showing the most recent 10 out of 202 publications