ABSTRACT
Obstructive sleep apnea (OSA) is a common condition affecting >10% of the adult population and 2-3%
of children in the USA. OSA is considered as an independent risk factor for the development of cardiovascular
and lung disorders but the underlying mechanisms are still largely unknown. In particular, the role of
intermittent hypoxia and hypercapnia (IHC, the integral components of OSA) in inducing or promoting
cardiovascular conditions remains obscure. Recent advances in sequencing technology and microbial and
metabolomic bioinformatics have shed light on an important relation between the gut microbiome and
cardiovascular diseases. Since OSA is a critical risk factor for these disorders, and our preliminary studies
have demonstrated that IHC alters the ecology of gut microbiome and have a strong impact on metabolism, we
hypothesize that IHC induces specific alterations in the gut microbiome and microbial-derived metabolites, and
these changes causally promote atherosclerosis. Indeed, we have obtained strong candidate microbial families
and metabolites that can affect vascular integrity under IHC. For example, we have found that a) IHC
accelerates the formation of atherosclerosis in ApoE-/- mice; b) IHC changes the gut microbiome ecology of
families such as Verrucomicrobiaceae, Ruminococcaceae and Erysipelotrichaceae; and c) IHC alters
microbial-derived metabolites (such as bile salts (BAs)). In the current application, we focus on these
microbiota and metabolite candidates to investigate their role in atherosclerosis. First, we will isolate specific
gut microbial strains that were altered by IHC treatment and determine the role of these specific microbial
strain(s) in the development of cardiovascular disease in vivo using germ-free ApoE-/- mice that were currently
created and established in our laboratory. Second, we will delineate the role of the major bile acid receptors
(i.e., FXR and TGR5) in mediating the effect of candidate bile acids in IHC-induced cardiovascular disease in
vivo using ApoE-/-/FXR-/- and ApoE-/-/TGR5-/- double knockout mice strains as well as the mice strains carrying
cell specific conditional deletion of FXR and TGR5 on ApoE-/- background. And third, we will dissect the
mechanisms underlying the role of specific IHC-altered bile acids (i.e., TßMCA and UDCA) in IHC-induced
macrophage foam cell formation in vitro using primary cell cultures that are derived from mice with ApoE-/-
/FXR-/- and ApoE-/-/TGR5-/- double deletion. This project will delineate novel mechanisms regulating OSA-
induced cardiovascular disease and provide potential novel targets and strategies to improve treatment or
prevent disease.