Disturbed flow induces systemic changes in metabolites in mouse plasma: a metabolomics study using ApoE⁻/⁻ mice with partial carotid ligation.
Disturbed blood flow (d-flow) occurring in branched and curved arteries promotes endothelial dysfunction and atherosclerosis, in part, by altering gene expression and epigenomic profiles in endothelial cells. While a systemic metabolic change is known to play a role in atherosclerosis, it is unclear whether it can be regulated by local d-flow. Here, we tested this hypothesis by carrying out a metabolomics study using blood plasma samples obtained from ApoE(-/-) mice that underwent a partial carotid ligation surgery to induce d-flow. Mice receiving sham ligation were used as a control. To study early metabolic changes, samples collected from 1 wk after partial ligation when endothelial dysfunction occurs, but before atheroma develops, were analyzed by high-resolution mass spectrometry. A metabolome-wide association study showed that 128 metabolites were significantly altered in the ligated mice compared with the sham group. Of these, sphingomyelin (SM; m/z 703.5747), a common mammalian cell membrane sphingolipid, was most significantly increased in the ligated mice. Of the 128 discriminatory metabolites, 18 and 41 were positively and negatively correlated with SM, respectively. The amino acids methionine and phenylalanine were increased by d-flow, while phosphatidylcholine and phosphatidylethanolamine were decreased by d-flow, and these metabolites were correlated with SM. Other significantly affected metabolites included dietary and environmental agents. Pathway analysis showed that the metabolic changes of d-flow impacted broad functional networks. These results suggest that signaling from d-flow occurring in focal regions induces systemic metabolic changes associated with atherosclerosis.
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia;
Young-Mi
YM
Go
Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia.
Chan Woo
CW
Kim
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia; Department of Civil and Environmental Engineering, Tufts University, Medford, Massachusetts; and.
Douglas I
DI
Walker
Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia.
Dong Won
DW
Kang
Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia.
Sandeep
S
Kumar
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia;
Michael
M
Orr
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia;
Karan
K
Uppal
Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia;
Arshed A
AA
Quyyumi
Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia.
Hanjoong
H
Jo
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia; dpjones@emory.edu.
Dean P
DP
Jones
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D015415:Biomarkers / Q000097:blood*; D002339:Carotid Arteries / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D002340:Carotid Artery Diseases / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D016893:Carotid Stenosis / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D008026:Ligation; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods; D008715:Methionine / Q000097:blood; D018345:Mice, Knockout; D010649:Phenylalanine / Q000097:blood; D010713:Phosphatidylcholines / Q000097:blood; D010714:Phosphatidylethanolamines / Q000097:blood; D012039:Regional Blood Flow; D013109:Sphingomyelins / Q000097:blood; D013997:Time Factors
D001057:Apolipoproteins E; D015415:Biomarkers; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D013109:Sphingomyelins; C483858:phosphatidylethanolamine; D010649:Phenylalanine; D008715:Methionine
atherosclerosis; disturbed blood flow; high-resolution metabolomics; metabolome-wide association study; sphingomyelin