Obesity leads to high cardiovascular morbidity and mortality acting via multiple mechanisms including increased prevalence and severity of hypertension and obstructive sleep apnea (OSA). Our main thesis is that obesity exacerbates hypertension and OSA acting via increased levels of an adipocyte produced hormone leptin, a potent stimulator of the sympathetic nervous system (SNS). Hyperleptinemia is associated with hypertension and overactive hypoxic ventilatory response (HVR), which may exacerbate comorbid OSA. The progression of OSA would further aggravate hypertension. We propose a novel mechanism that leptin acts peripherally on the carotid bodies (CB) to exert SNS and HVR effects. CB are major peripheral hypoxia sensors sensitized by obesity and OSA. Our preliminary data show that (1) leptin stimulates CB via non- selective cation transient receptor potential channel melastatin 7 (TRPM7), that (2) leptin regulates HVR and this effect is abolished by TRPM7 blockers; (3) leptin induces hypertension and this effect is abolished by CSN denervation; (4) replenishment of leptin ObRb receptor in CB of leptin receptor deficient db/db mice increases Trpm7 expression and HVR exacerbating sleep apnea. Our overarching hypothesis is that leptin augments the CB chemoreflex acting via TRPM7 channels to exacerbate OSA and induce hypertension. We propose a multidisciplinary approach using electrophysiological, molecular and epigenetic techniques, as well as advance techniques for continuous recording of sleep apnea and cardiovascular variables in CB-targeted mouse models.
Specific Aim 1 will determine the mechanisms by which leptin augments CB activity. We will examine whether (A) leptin signaling acutely increases TRPM7 channel activity, leading to increase in [Ca2+]i and membrane depolarization in the CB glomus cells and augmenting CB chemoreceptor response; and (B) prolonged exposure to leptin chronically upregulates Trpm7 transcription via epigenetic mechanisms.
Specific Aim 2 will determine the mechanisms by which leptin affects the CB chemoreflex and sleep apnea. We will examine the effects of leptin on CB chemo reflex and sleep apnea in mice by using (A) mice with CB specific leptin ObRb receptor overexpression and knockout; and (B) mice with CB specific Trpm7 gene knockout or treated with TRPM7 inhibitors.
Specific Aim 3 will determine the mechanisms by which leptin signaling in CB affects blood pressure. We will examine the effects of leptin on continuously monitored blood pressure (A) in mice with CB specific ObRb overexpression and knockout; (B) in mice with CB specific Trpm7 gene knockout and in mice treated with TRPM7 inhibitors. This project will have a significant impact by defining a novel concept of hormonal regulation of the CB functions and the pathogenesis of hypertension and sleep apnea in obesity. The successful implementation of our proposal will identify novel therapeutic targets for the treatment of hypertension and sleep apnea.
Obesity leads to high cardiovascular morbidity and mortality acting via multiple mechanisms including increased prevalence and severity of hypertension and obstructive sleep apnea, which are frequently inadequately controlled. We have discovered a novel mechanism of hypertension and sleep apnea in obesity related to signaling of obesity hormone leptin in the carotid body, a peripheral sensor of insufficient oxygen in the blood. This signaling pathway occurs via a specific channel TRPM7 and we propose that blocking TRPM7 in the carotid body of obese patients will treat hypertension and sleep apnea, which would have a profound impact on the public health.
| Fleury Curado, Thomaz; Berger, Slava; Polotsky, Vsevolod Y (2018) Pharmacotherapy of Obstructive Sleep Apnea: Is Salvation Just Around a Corner? Am J Respir Crit Care Med : |
| Pham, Luu V; Schwartz, Alan R; Polotsky, Vsevolod Y (2018) Integrating loop gain into the understanding of obstructive sleep apnoea mechanisms. J Physiol 596:3819-3820 |
| Fleury Curado, Thomaz; Pho, Huy; Berger, Slava et al. (2018) Sleep-disordered breathing in C57BL/6J mice with diet-induced obesity. Sleep 41: |
| Berger, Slava; Pho, Huy; Fleury-Curado, Thomaz et al. (2018) Intranasal Leptin Relieves Sleep Disordered Breathing in Mice with Diet Induced Obesity. Am J Respir Crit Care Med : |
| Berger, Slava; Polotsky, Vsevolod Y (2018) Leptin and Leptin Resistance in the Pathogenesis of Obstructive Sleep Apnea: A Possible Link to Oxidative Stress and Cardiovascular Complications. Oxid Med Cell Longev 2018:5137947 |
| Drager, Luciano F; Tavoni, Thauany M; Silva, Vanessa M et al. (2018) Obstructive sleep apnea and effects of continuous positive airway pressure on triglyceride-rich lipoprotein metabolism. J Lipid Res 59:1027-1033 |
| Fleury Curado, Thomaz; Oliven, Arie; Sennes, Luiz U et al. (2018) Neurostimulation Treatment of OSA. Chest 154:1435-1447 |
| Fleury Curado, Thomaz A; Pho, Huy; Dergacheva, Olga et al. (2018) Silencing of Hypoglossal Motoneurons Leads to Sleep Disordered Breathing in Lean Mice. Front Neurol 9:962 |
| Javaheri, Shahrokh; Barbe, Ferran; Campos-Rodriguez, Francisco et al. (2017) Sleep Apnea: Types, Mechanisms, and Clinical Cardiovascular Consequences. J Am Coll Cardiol 69:841-858 |
| Fleury Curado, Thomaz; Fishbein, Kenneth; Pho, Huy et al. (2017) Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency. Sci Rep 7:44392 |
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