Intermittent Hypoxia and Hypercapnia Accelerate Aorta and Pulmonary Artery Atherosclerosis, partially Mediated via Trimethylamine‐Oxide (TMAO) in both ApoE−/− and Ldlr−/− Mice on High Fat Diet

Abstract

Obstructive sleep apnea (OSA) is a common disorder characterized by intermittent hypoxia and hypercapnia (IHC) during sleep and is often associated with increased inflammation, oxidative stress and dyslipidemia. Clinical studies have shown that OSA is an independent risk factor for atherosclerosis. To dissect the mechanisms involved, we compared the development of atherosclerotic lesions between two mouse models of atherosclerosis, i.e., the apolipoprotein E (ApoE) and the 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 wks while being exposed to IHC 10 hr/day or normoxia 24 hr/day. En face lesions of the entire aorta, aortic arch and pulmonary artery (PA) were then examined. In addition, 3,3‐dimethyl‐1‐butanol (DMB), an inhibitor of microbial TMA production, was used to determine the contribution of microbes and TMAO in IHC‐induced atherosclerosis. The results showed that (1) 8‐week IHC exposure expedited high fat diet‐induced 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 Normoxia 8.0±2.8%, p<0.01); (2) the atherosclerotic lesions evolved faster and to a more severe extent in ApoE−/− mice as compared to those in Ldlr−/− mice (PA IHC 8wks, ApoE−/− 35.4±1.9% vs Ldlr−/− 8.2±1.5%, p<0.01); (3) DMB significantly attenuated IHC‐induced PA atherosclerosis but did not eliminate totally lesion formation induced by IHC (ApoE−/− PA 8wks, IHC DMB 25.6±2.6% either vs IHC 35.4±1.9%, p<0.01 or vs Normoxia 8.0±2.8%, p<0.01). Taken together, our findings suggest that IHC, a hallmark of OSA, accelerates the progression of atherosclerosis, in both vascular beds but especially in PA. This process is partly inhibited by a non‐lethal microbial TMA lyase inhibitor, suggesting the involvement of microbes and their metabolites TMA and TMAO, which may serve as potential therapeutic targets for the prevention and treatment of OSA‐induced atherosclerosis.