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

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

Am J Respir Cell Mol Biol. 2017 Jul 05;:

Authors: Xue J, Zhou D, Poulsen O, Imamura T, Hsiao YH, Smith TH, Malhotra A, Dorrestein P, Knight R, Haddad GG

Abstract
RATIONALE: Obstructive sleep apnea (OSA) is a common disorder characterized by intermittent hypoxia and hypercapnia (IHC) during sleep. OSA has been shown as a risk factor for atherosclerosis but the relation of IHC to induction or progression of atherosclerosis is not well understood. To dissect the mechanisms involved, we compared atherosclerotic formation between two mouse models, i.e., the apolipoprotein E (ApoE) and the low density lipoprotein receptor (Ldlr) deficient mice, with or without IHC exposure.
METHODS: Ten-week-old ApoE-/- or Ldlr-/- mice were fed a high-fat diet for 4 or 8 wks while being exposed to IHC 10 hrs/day or room air (RA) 24 hrs/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 oxidized TMA (TMAO) in IHC-induced atherosclerosis.
RESULTS: Eight-week IHC exposure expedited the formation of atherosclerosis in both PA and aortic arch of ApoE-/- mice but only in PA of Ldlr-/- mice (ApoE-/- PA 8wks, IHC 35.4±1.9% vs RA 8.0±2.8%, p<0.01). The atherosclerotic lesions evolved faster and severely in ApoE-/- mice as compared to Ldlr-/- mice (PA IHC 8wks, ApoE-/- 35.4±1.9% vs Ldlr-/- 8.2±1.5%, p<0.01). DMB significantly attenuated though did not totally eliminate IHC-induced PA atherosclerosis.
CONCLUSIONS: Our findings suggest that IHC, a hallmark of OSA, accelerates the progression of atherosclerosis, in aorta and especially in PA. This process is partly inhibited by DMB, demonstrating that microbial metabolites may serve as therapeutic targets for OSA-induced atherosclerosis.

PMID: 28678519 [PubMed - as supplied by publisher]

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