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 TNF alpha and IL-beta. 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-B-3, 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-B-3 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.
[1]Peking Univ, Hlth Sci Ctr, Dept Physiol & Pathophysiol, Beijing 100191, Peoples R China.
[2]Univ Chinese Acad Sci, CAS Key Lab Magnet Resonance Biol Syst, State Key Lab Magnet Resonance & Atom & Mol Phys, Natl Ctr Magnet Resonance Wuhan,Wuhan Inst Phys &, Wuhan 430071, Peoples R China.
[3]Fudan Univ, State Key Lab Genet Engn, Collaborat Innovat Ctr Genet & Dev, Metabon & Syst Biol Lab,Sch Life Sci, Shanghai 200433, Peoples R China.
[4]Zhejiang Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Hangzhou 310058, Zhejiang, Peoples R China.
[5]Tianjin Med Univ, Dept Physiol & Pathophysiol, Tianjin 300070, Peoples R China.
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