title: Metabonomic Changes Associated with Atherosclerosis Progression for LDLR(-/-) Mice.
abstract: Atherosclerosis resulting from hyperlipidemia causes many serious cardiovascular diseases. To understand the systems changes associated with pathogenesis and progression of atherosclerosis, we comprehensively analyzed the dynamic metabonomic changes in multiple biological matrices of LDLR(-/-) mice using NMR and GC-FID/MS with gene expression, clinical chemistry, and histopathological data as well. We found that 12 week "Western-type" diet (WD) treatment caused obvious aortic lesions, macrophage infiltration, and collagen level elevation in LDLR(-/-) mice accompanied by up-regulation of inflammatory factors including aortic ICAM-1, MCP-1, iNOS, MMP2, and hepatic TNFα and IL-1β. The WD-induced atherosclerosis progression was accompanied by metabonomic changes in multiple matrices including biofluids (plasma, urine) and (liver, kidney, myocardial) tissues involving multiple metabolic pathways. These included disruption of cholesterol homeostasis, disturbance of biosynthesis of amino acids and proteins, altered gut microbiota functions together with metabolisms of vitamin-B3, choline, purines, and pyrimidines. WD treatment caused down-regulation of SCD1 and promoted oxidative stress reflected by urinary allantoin elevation and decreases in hepatic PUFA-to-MUFA ratio. When switching to normal diet, atherosclerotic LDLR(-/-) mice reprogrammed their metabolisms and reversed the atherosclerosis-associated metabonomic changes to a large extent, although aortic lesions, inflammation parameters, macrophage infiltration, and collagen content were only partially alleviated. We concluded that metabolisms of fatty acids and vitamin-B3 together with gut microbiota played crucially important roles in atherosclerosis development. These findings offered essential biochemistry details of the diet-induced atherosclerosis and demonstrated effectiveness of the integrated metabonomic analysis of multiple biological matrices for understanding the molecular aspects of cardiovascular diseases.
authors.affiliation: †Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: ‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: ‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.
authors.forename: Fangcong
authors.initials: F
authors.lastname: Dong
authors.affiliation: †Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: ‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: ‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Li
authors.affiliation: ‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.
authors.forename: Hehua
authors.initials: H
authors.lastname: Lei
authors.affiliation: ‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.
authors.forename: Fuhua
authors.initials: F
authors.lastname: Hao
authors.affiliation: ‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.|∥Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: †Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.|⊥Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: ‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.|§State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Metabonomics and Systems Biology Laboratory, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Huiru
authors.initials: H
authors.lastname: Tang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D055442:Metabolome / Q000235:genetics*; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005227:Fatty Acids; D053583:Interleukin-1beta; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: LDLR−/− mice; NMR; atherosclerosis; gut microbiota; high-fat diet; metabonomics