Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis

Gautier-Veyret, Élodie; Arnaud, Claire; Bäck, Magnus; Pépin, Jean‐Louis; Petri, Marcelo H.; Baguet, Jean-Philippe; Tamisier, Renaud; Lévy, Patrick; Stanke‐Labesque, Françoise

doi:10.1183/09031936.00096512

Cited by 43 publications

(40 citation statements)

References 33 publications

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“…They exposed apolipoprotein E-deficient mice (a model of severe hyperlipidemia, used to show acceleration of atherosclerosis during intermittent hypoxia [93]) to 8 weeks of intermittent hypoxia (IH). IH increased atherosclerotic plaques in association with increased COX-1 and thromboxane synthesis expression, while pharmacologic blockade of COX-1 attenuated the effects of IH [94]. However, urine 11-dehydroxythromboxane (a metabolite of thromboxane A 2 ) was not increased in patients with OSA unless they also had underlying cardiovascular risk factors; and CPAP did not affect 11-dehydroxythromboxane levels.…”

Section: Osa and Inflammation – Novel Biomarkersmentioning

confidence: 99%

Inflammation in sleep apnea: An update

Unnikrishnan

Jun

Polotsky

2014

Rev Endocr Metab Disord

165

118

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Obstructive sleep apnea (OSA) is a common disorder associated with cardiovascular disease (CVD). One theory to explain this relationship proposes that OSA can induce systemic inflammation, thereby inducing CVD. This theory is based on the premise that obesity is a pro-inflammatory state, and that physiological derangements during sleep in subjects with OSA further aggravate inflammation. In support of this theory, some clinical studies have shown elevated inflammatory biomarkers in OSA subjects, or improvement in these markers following treatment of OSA. However, the data are inconsistent and often confounded by the effects of comorbid obesity. Animal models of OSA have been developed, which involve exposure of rodents or cells to intermittent hypoxia, a hallmark feature of OSA. Several of these experiments demonstrate that intermittent hypoxia can stimulate inflammatory pathways and lead to cardiovascular or metabolic pathology. In this review, we review relationships between OSA and inflammation, with particular attention to studies published within the last year.

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Section: Osa and Inflammation – Novel Biomarkersmentioning

confidence: 99%

Inflammation in sleep apnea: An update

Unnikrishnan

Jun

Polotsky

2014

Rev Endocr Metab Disord

165

118

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“…With IH, prostanoid concentrations are shifted towards vasoconstriction and atherogenesis . However, whether this concentration shift is involved in IH‐induced increases in blood pressure, and altered cerebral blood flow (CBF) regulation, is not known.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenases 1 and 2 Differentially Regulate Blood Pressure and Cerebrovascular Responses to Acute and Chronic Intermittent Hypoxia: Implications for Sleep Apnea

Beaudin

Pun

Yang

et al. 2014

JAHA

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BackgroundObstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)‐induced inflammation. Cyclooxygenase (COX)‐formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure and CBF responses to IH is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to IH.Methods and ResultsTwelve healthy, male participants underwent three, 6‐hour IH exposures. For 4 days before each IH exposure, participants ingested a placebo, indomethacin (nonselective COX inhibitor), or Celebrex® (selective COX‐2 inhibitor) in a double‐blind, randomized, crossover study design. Pre‐ and post‐IH blood pressure, CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated OSA patients (n=33). Nonselective COX inhibition increased pre‐IH blood pressure (P≤0.04) and decreased pre‐IH CBF (P=0.04) while neither physiological variable was affected by COX‐2 inhibition (P≥0.90). Post‐IH, MAP was elevated (P≤0.05) and CBF was unchanged with placebo and nonselective COX inhibition. Selective COX‐2 inhibition abrogated the IH‐induced MAP increase (P=0.19), but resulted in lower post‐IH CBF (P=0.01). Prostanoids were unaffected by IH, except prostaglandin E2 was elevated with the placebo (P=0.02). Finally, OSA patients had elevated blood pressure (P≤0.4) and COX‐1 formed thromboxane A2 concentrations (P=0.02).ConclusionsCOX‐2 and COX‐1 have divergent roles in modulating vascular responses to acute and chronic IH. Moreover, COX‐1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in OSA.Clinical Trial RegistrationURL: www.clinicaltrials.gov. Unique identifier: NCT01280006

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“…I ntermittent hypoxia during sleep (IH) is one of the hallmarks of obstructive sleep apnea (OSA) and induces a wide range of morbid consequences, including excessive daytime sleepiness and cognitive, mood, and neurobehavioral deficits (1)(2)(3)(4)(5)(6), as well as cardiovascular dysfunction (7)(8)(9)(10). IH also imposes adverse metabolic consequences, such as hyperlipidemia and insulin resistance, even in lean mice, along with structural and cellular remodeling of adipose tissue (11)(12)(13)(14)(15)(16)(17)(18).…”

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confidence: 99%

Resveratrol Attenuates Intermittent Hypoxia-Induced Macrophage Migration to Visceral White Adipose Tissue and Insulin Resistance in Male Mice

et al. 2014

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Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

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Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis

Cited by 43 publications

References 33 publications

Inflammation in sleep apnea: An update

Inflammation in sleep apnea: An update

Cyclooxygenases 1 and 2 Differentially Regulate Blood Pressure and Cerebrovascular Responses to Acute and Chronic Intermittent Hypoxia: Implications for Sleep Apnea

Resveratrol Attenuates Intermittent Hypoxia-Induced Macrophage Migration to Visceral White Adipose Tissue and Insulin Resistance in Male Mice

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