Obstructive sleep apnea, the microbiome and cardiovascular disease

阻塞性睡眠呼吸暂停、微生物组和心血管疾病

• 批准号: 10544020
• 负责人: Gabriel G Haddad
• 金额: $ 72.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544020
• 关键词: Acceleration; Adult; Affect; Apolipoprotein E; Atherosclerosis; Bile Acids; Bioinformatics; Blood; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Child; Development; Disease; Ecology; Exposure to; Family; Foam Cells; GPBAR1 gene; Germ-Free; Human; Hypercapnia; Hypoxia; In Vitro; Knock-out; Knockout Mice; Knowledge; Laboratories; Low-Density Lipoproteins; Lung diseases; Macrophage; Macrophage Activation; Mediating; Metabolism; Metagenomics; Mouse Strains; Mus; Myocardial Infarction; Obesity; Obstructive Sleep Apnea; Peritoneal Macrophages; Play; Population; Primary Cell Cultures; Risk Factors; Role; Sleep Disorders; Stroke; Technology; Testing; atherogenesis; bile salts; cardiovascular disorder prevention; cardiovascular risk factor; gut bacteria; gut microbiome; improved; in vivo; insight; metabolome; metabolomics; microbial; microbiome; microbiota; new therapeutic target; novel; oxidized low density lipoprotein; prevent; receptor; reverse cholesterol transport; uptake

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., TβMCA 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.

摘要