Leptin and intermittent hypoxia interactions in the carotid bodies: mechanisms and consequences

George Washington University, Washington DC

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Abstract

Obstructive sleep apnea (OSA) is recurrent closure of upper airway during sleep, which results in intermittent hypoxia (IH). OSA is the most common type of sleep disordered breathing (SDB), which is particularly prevalent in obesity affecting more than 50% individuals with BMI ≥ 30 kg/m2. OSA is a leading cause of hypertension with IH playing a major role. IH activates the sympathetic nervous system (SNS) inducing hypertension in humans and animal models. IH-induced activation of SNS originates in the carotid body (CB), a peripheral sensor of hypoxia, which provides key afferent input to medullary network that regulates SNS activity. Obesity also activates SNS and causes hypertension. CB plays a role in obesity-induced hypertension. Interactions between IH and obesity in CB, which are highly translationally relevant in SDB, have not been explored. This project will examine novel molecular targets in the CB differentially regulated by IH and obesity to optimize treatment of cardiovascular complications of OSA. During the previous funding periods of this award we identified a pathway by which obesity increases CB and carotid sinus nerve (CSN) activity leading to hypertension. Specifically, we have shown that obesity-induced hypertension is a consequence of leptin binding to the leptin receptor LEPRb on hypoxia-sensing tyrosine hydroxylase (TH) positive CB type I cells, which leads to up-regulation of the transient receptor potential melastatin-subfamily member 7 (TRPM7). Our Preliminary Data demonstrate that IH increases expression of TRPM7 in CB and CSN activity and that pharmacological and genetic blockade of CB TRPM7 abolishes IH-induced hypertension. We have shown that both leptin and IH increase CB TRPM7 gene expression via epigenetic modifications including DNA demethylation of Trpm7 gene promoter. We identified three differentially methylated regions (DMRs) in the Trpm7 promoter, which can be demethylated by 5-aza- deoxycytidine. We demonstrated that DMR region 1 (R1) is selectively demethylated by obesity via the leptin- LEPRb mechanism, while the DMR region 2 (R2) and DMR region 3 (R3) are demethylated by IH. Furthermore, we provide preliminary data that targeted methylation of these regions in vivo greatly decreases Trpm7 gene expression in CB and decreases CSN activity and blood pressure. Our overarching hypothesis is that obesity and IH interact to induce epigenetic up-regulation of Trpm7 gene expression in CB and increase CSN and SNS activity leading to hypertension. We will use our mouse models of DIO and IH, wildtype and transgenic mouse strains to address this hypothesis in four aims. Specific Aims 1 and 2 will examine how IH and obesity interact on the CB TRPM7 to induce hypertension (Aim 1) and CSN/SNS activity (Aim 2) using genetic and pharmacological blockade of LEPRb and TRPM7 in CB. Specific Aims 3 and 4 will examine how IH and obesity affect methylation of the Trpm7 promoter in CB to induce hypertension (Aim 3) and CSN/SNS activity (Aim 4) using methylated oligonucleotides complementary to the DMRs R1, R2, and R3. Our proposal will contribute to pharmacotherapy of obesity and OSA and open new horizons for translational use of epigenetics.