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Am J Respir Cell Mol Biol. 2017 Nov;57(5):581-588. doi: 10.1165/rcmb.2017-0086OC.

Intermittent Hypoxia and Hypercapnia Accelerate Atherosclerosis, Partially via Trimethylamine-Oxide.

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Departments of 1 Pediatrics.
2 Internal Medicine, and.
3 Neurosciences, School of Medicine.
4 School of Pharmacy and Pharmaceutical Sciences, and.
5 Department of Computer Sciences and Engineering, School of Engineering, University of California San Diego, La Jolla, California; and.
6 The Rady Children's Hospital, San Diego, California.


Obstructive sleep apnea (OSA) is a common disorder characterized by intermittent hypoxia and hypercapnia (IHC) during sleep. OSA has been shown to be a risk factor for atherosclerosis, but the relation of IHC to the induction or progression of atherosclerosis is not well understood. To dissect the mechanisms involved, we compared atherosclerotic lesion formation in two mouse models, i.e., apolipoprotein E (ApoE) and low density lipoprotein receptor (Ldlr)-deficient mice, with or without IHC exposure. Ten-week-old ApoE-/- or Ldlr-/- mice were fed a high-fat diet for 4 or 8 weeks while being exposed to IHC for 10 hours/day or room air (RA) for 24 hours/day. En face lesions of the aorta, aortic arch, and pulmonary artery (PA) were examined. Moreover, 3,3-dimethyl-1-butanol (DMB), an inhibitor of microbial trimethylamine (TMA) production, was used to determine the contribution of TMA-oxide (TMAO) to IHC-induced atherosclerosis. Eight weeks of IHC exposure expedited the formation of atherosclerosis in both the PA and aortic arch of ApoE-/- mice, but only in the PA of Ldlr-/- mice (ApoE-/- PA 8 wk, IHC 35.4 ± 1.9% versus RA 8.0 ± 2.8%, P < 0.01). The atherosclerotic lesions evolved faster and to a more severe extent in ApoE-/- mice as compared with Ldlr-/- mice (PA IHC 8 wk, ApoE-/- 35.4 ± 1.9% versus Ldlr-/- 8.2 ± 1.5%, P < 0.01). DMB significantly attenuated but did not totally eliminate IHC-induced PA atherosclerosis. Our findings suggest that IHC, a hallmark of OSA, accelerates the progression of atherosclerosis in the aorta and especially in the PA. This process is partly inhibited by DMB, demonstrating that microbial metabolites may serve as therapeutic targets for OSA-induced atherosclerosis.


atherosclerosis; intermittent hypoxia and hypercapnia; microbes; obstructive sleep apnea

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