title: Proteomic and metabolomic analysis of smooth muscle cells derived from the arterial media and adventitial progenitors of apolipoprotein E-deficient mice.
abstract: We have recently demonstrated that stem cell antigen 1-positive (Sca-1(+)) progenitors exist in the vascular adventitia of apolipoprotein E-deficient (apoE(-/-)) mice and contribute to smooth muscle cell (SMC) accumulation in vein graft atherosclerosis. Using a combined proteomic and metabolomic approach, we now characterize these local progenitors, which participate in the formation of native atherosclerotic lesions in chow-fed apoE(-/-) mice. Unlike Sca-1(+) progenitors from embryonic stem cells, the resident Sca-1(+) stem cell population from the vasculature acquired a mature aortic SMC phenotype after platelet-derived growth factor-BB stimulation. It shared proteomic and metabolomic characteristics of apoE(-/-) SMCs, which were clearly distinct from wild-type SMCs under normoxic and hypoxic conditions. Among the differentially expressed proteins were key enzymes in glucose metabolism, resulting in faster glucose consumption and a compensatory reduction in baseline interleukin-6 secretion. The latter was associated with a marked upregulation of insulin-like growth factor binding proteins (IGFBPs) 3 and 6. Notably, reconstitution of interleukin-6 to levels measured in the conditioned medium of wild-type SMCs attenuated the elevated IGFBP expression in apoE(-/-) SMCs and their vascular progenitors. This coregulation of apoE, interleukin-6, and IGFBPs was replicated in wild-type SMCs from hypercholesterolemic mice and confirmed by silencing apoE expression in SMCs from normocholesterolemic mice. In summary, we provide evidence that Sca-1(+) progenitors contribute to native atherosclerosis in apoE(-/-) mice, that apoE deficiency and hypercholesterolemia alter progenitor cell behavior, and that inflammatory cytokines such as interleukin-6 act as metabolic regulators in SMCs of hyperlipidemic mice.
authors.affiliation: Cardiovascular Division, The James Black Centre, King's College, University of London, 125 Coldharbour Ln, London SE5 9NU, United Kingdom. manuel.mayr@kcl.ac.uk
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Anna
authors.initials: A
authors.lastname: Zampetaki
authors.forename: Anissa
authors.initials: A
authors.lastname: Sidibe
authors.forename: Ursula
authors.initials: U
authors.lastname: Mayr
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.forename: Ayesha I
authors.initials: AI
authors.lastname: De Souza
authors.forename: Yuen-Li
authors.initials: YL
authors.lastname: Chung
authors.forename: Basetti
authors.initials: B
authors.lastname: Madhu
authors.forename: Paul H
authors.initials: PH
authors.lastname: Quax
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.forename: John R
authors.initials: JR
authors.lastname: Griffiths
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001158:Arteries / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000067696:Ataxin-1; D000067528:Ataxins; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077214:Becaplermin; D001681:Biological Assay; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003238:Connective Tissue / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005947:Glucose / Q000378:metabolism; D006937:Hypercholesterolemia / Q000378:metabolism; D015151:Immunoblotting; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D020574:Proto-Oncogene Proteins c-sis; D013234:Stem Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D053719:Tandem Mass Spectrometry; D017540:Tunica Media / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D018969:Insulin-Like Growth Factor Binding Proteins; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D005947:Glucose