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dc.contributor.authorVerdeguer, Francisco-
dc.contributor.authorCastro, Claudia-
dc.contributor.authorKubicek, Markus-
dc.contributor.authorPla, Davinia-
dc.contributor.authorVila-Caballer, Marian-
dc.contributor.authorVinué, Ángela-
dc.contributor.authorCiveira, Fernando-
dc.contributor.authorPocoví, Miguel-
dc.contributor.authorCalvete, Juan J.-
dc.contributor.authorAndrés, Vicente-
dc.identifier.citationCardiovasc Res 76 (2):340-350en_US
dc.descriptionThis is a pre-copy-editing, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The definitive publisher-authenticated version Cardiovasc Res. 76 (2):340-350 is available online at: http://cardiovascres.oxfordjournals.org/cgi/content/full/76/2/340en_US
dc.description.abstractOBJECTIVE: Mounting evidence suggests that activation of complement, an important constituent of innate immunity, contributes to atherosclerosis. Here we investigated the expression of complement components (CCs) in the setting of experimental and clinical hypercholesterolemia, a major risk factor for atherosclerosis, their effects on vascular smooth muscle cell (VSMC) and macrophage proliferation, and the underlying molecular mechanisms. METHODS: For this study we analyzed the mRNA and protein expression of several CCs in plasma and aorta of hypercholesterolemic atherosclerosis-prone apolipoprotein E-null mice (apoE-KO) and in plasma of normocholesterolemic subjects and familial hypercholesterolemia (FH) patients. We also carried out in vitro molecular studies to assess the role of CCs on the control of macrophage and VSMC proliferation. RESULTS: Fat-fed apoE-KO mice experiencing severe hypercholesterolemia (~400 mg/dL), but not fat-fed wild-type controls with plasma cholesterol level <110 mg/dL, displayed in aortic tissue upregulation of several CC mRNAs, including C3, C4, C1s, and C1q. In apoE-KO mice, induction of C3 mRNA was already apparent two days after fat feeding when hypercholesterolemia was manifest yet atherosclerotic lesions were absent or incipient. Rapid C3 and C4 protein upregulation was also observed in the plasma of fat-fed apoE-KO mice, and FH patients exhibited higher plasmatic C3a, C4 γ chain, C1s and C3c α chain protein levels than normocholesterolemic subjects. In vitro, C3 and C3a, but not C3a-desArg, C4 and C1q, promoted macrophage and VSMC proliferation through Gi protein-dependent activation of extracellular signalregulated kinase 1/2 (ERK1/2). We also found that C3-enriched FH plasma evoked a stronger mitogenic response in macrophages than normocholesterolemic plasma, and treatment with anti-C3 antibodies eliminated this difference. CONCLUSIONS: Both experimental and clinical hypercholesterolemia coincides with a concerted activation of several CCs. However, only C3 and C3a elicited a mitogenic response in cultured VSMCs and macrophages through Gi protein-dependent ERK1/2 activation. Thus, excess of C3/C3a in hypercholesterolemic apoE-KO mice and FH patients may contribute to atheroma growth by promoting neointimal cell proliferation.en_US
dc.description.sponsorshipWork supported by Laboratorios INDAS, Instituto de Salud Carlos III - Ministerio de Sanidad y Consumo of Spain (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares -RECAVA, and predoctoral fellowship to F.V.), Ministerio de Educación y Ciencia of Spain and European Regional Development Fund (grants SAF2004-03057 and BFU2004-01432, predoctoral FPI fellowship to D.P.), European Commission (Marie Curie postdoctoral fellowship to M.K.), Fundación Carolina (postdoctoral fellowship to C.C.), and Regional Government of Valencia (predoctoral fellowship to M.V.-C.).en_US
dc.format.extent1815412 bytes-
dc.publisherOxford University Pressen_US
dc.subjectComplement activationen_US
dc.subjectVascular smooth muscle cellen_US
dc.titleComplement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferationen_US
dc.description.peerreviewedPeer revieweden_US
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