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.
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.
|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|
|Cundrle Jr, Ivan; Somers, Virend K; Singh, Prachi et al. (2017) Low leptin concentration may identify heart failure patients with central sleep apnea. J Sleep Res :|
|Gottlieb, Daniel J; Somers, Virend K; Punjabi, Naresh M et al. (2017) Restless legs syndrome and cardiovascular disease: a research roadmap. Sleep Med 31:10-17|
|Medina-Inojosa, Jose; Somers, Virend; Jenkins, Sarah et al. (2017) Validation of a White-light 3D Body Volume Scanner to Assess Body Composition. Obes Open Access 3:|
|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:|
|Medina-Inojosa, Jose; Somers, Virend K; Ngwa, Taiwo et al. (2016) Reliability of a 3D Body Scanner for Anthropometric Measurements of Central Obesity. Obes Open Access 2:|
|Singh, P; Sharma, P; Sahakyan, K R et al. (2016) Differential effects of leptin on adiponectin expression with weight gain versus obesity. Int J Obes (Lond) 40:266-74|
|Iturriaga, Rodrigo; Del Rio, Rodrigo; Idiaquez, Juan et al. (2016) Carotid body chemoreceptors, sympathetic neural activation, and cardiometabolic disease. Biol Res 49:13|
|Pusalavidyasagar, Snigdha; Sert Kuniyoshi, Fatima H; Shamsuzzaman, Abu S M et al. (2016) Comparison of Endothelial Function in Asian Indians Versus Caucasians. Metab Syndr Relat Disord 14:363-7|
|Covassin, Naima; Somers, Virend K (2016) Sleep apnea, hypertension, and hemorrhagic stroke-déjà vu all over again. J Am Soc Hypertens 10:197-200|
Showing the most recent 10 out of 195 publications