Proteomic and metabolomic analysis of smooth muscle cells derived from the arterial media and adventitial progenitors of apolipoprotein E-deficient mice.
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.
Mayr
Manuel
M
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
Zampetaki
Anna
A
Sidibe
Anissa
A
Mayr
Ursula
U
Yin
Xiaoke
X
De Souza
Ayesha I
AI
Chung
Yuen-Li
YL
Madhu
Basetti
B
Quax
Paul H
PH
Hu
Yanhua
Y
Griffiths
John R
JR
Xu
Qingbo
Q
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
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