Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation
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 atherosc...
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| Veröffentlicht in: | Cardiovascular research 2007-11, Vol.76 (2), p.340-350 |
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| creator | VERDEGUER, Francisco CASTRO, Claudia KUBICEK, Markus PLA, Davinia VILA-CABALLER, Marian VINUE, Angela CIVEIRA, Fernando POCOVI, Miguel CALVETE, Juan José ANDRES, Vicente |
| description | 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.
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.
Fat-fed apoE-KO mice experiencing severe hypercholesterolemia (approximately 400 mg/dL), but not fat-fed wild-type controls with plasma cholesterol level |
| doi_str_mv | 10.1016/j.cardiores.2007.06.028 |
| format | Article |
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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.
Fat-fed apoE-KO mice experiencing severe hypercholesterolemia (approximately 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 manifested 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 gamma chain, C1s and C3c alpha 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 signal-regulated 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.
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.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1016/j.cardiores.2007.06.028</identifier><identifier>PMID: 17673191</identifier><identifier>CODEN: CVREAU</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Amino Acid Sequence ; Animals ; Apolipoproteins E - physiology ; Biological and medical sciences ; Cardiology. Vascular system ; Cell Proliferation ; Complement C3 - physiology ; Complement C3a - physiology ; Complement System Proteins - physiology ; Disorders of blood lipids. Hyperlipoproteinemia ; Extracellular Signal-Regulated MAP Kinases - physiology ; GTP-Binding Protein alpha Subunits, Gi-Go - physiology ; Humans ; Hypercholesterolemia - etiology ; Macrophages - cytology ; Male ; Medical sciences ; Metabolic diseases ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Muscle, Smooth, Vascular - cytology ; Myocytes, Smooth Muscle - physiology</subject><ispartof>Cardiovascular research, 2007-11, Vol.76 (2), p.340-350</ispartof><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c456t-c881bcb24d40a11f8f8b5c93796319d5a06c2b992cdbea14aeb543090f2e93a73</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19171913$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17673191$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>VERDEGUER, Francisco</creatorcontrib><creatorcontrib>CASTRO, Claudia</creatorcontrib><creatorcontrib>KUBICEK, Markus</creatorcontrib><creatorcontrib>PLA, Davinia</creatorcontrib><creatorcontrib>VILA-CABALLER, Marian</creatorcontrib><creatorcontrib>VINUE, Angela</creatorcontrib><creatorcontrib>CIVEIRA, Fernando</creatorcontrib><creatorcontrib>POCOVI, Miguel</creatorcontrib><creatorcontrib>CALVETE, Juan José</creatorcontrib><creatorcontrib>ANDRES, Vicente</creatorcontrib><title>Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>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.
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.
Fat-fed apoE-KO mice experiencing severe hypercholesterolemia (approximately 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 manifested 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 gamma chain, C1s and C3c alpha 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 signal-regulated 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.
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.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Apolipoproteins E - physiology</subject><subject>Biological and medical sciences</subject><subject>Cardiology. Vascular system</subject><subject>Cell Proliferation</subject><subject>Complement C3 - physiology</subject><subject>Complement C3a - physiology</subject><subject>Complement System Proteins - physiology</subject><subject>Disorders of blood lipids. Hyperlipoproteinemia</subject><subject>Extracellular Signal-Regulated MAP Kinases - physiology</subject><subject>GTP-Binding Protein alpha Subunits, Gi-Go - physiology</subject><subject>Humans</subject><subject>Hypercholesterolemia - etiology</subject><subject>Macrophages - cytology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Molecular Sequence Data</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Myocytes, Smooth Muscle - physiology</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkc1u3SAQhVHVqLlN-gotm3ZnB4wBs6yu0h8pUjfNGmE8jrky4IK9yCP0rYtzr5rVMOI7ZxgOQp8oqSmh4u5UW5MGFxPkuiFE1kTUpOneoAOVnFesaflbdCCEdJVggl2j9zmfSsu5bN-hayqFZFTRA_p7jH6ZwUNYcYKnbTariwG7gP2WXABswoCnzZuAp-cFkp3iDHmFVIp35uV6P--KdQJsY1hLj-OIvbEpLpN5OptkH-M6FdtsC25hnvFSSDdCepl5i65GM2f4cKk36PHb_e_jj-rh1_efx68PlW25WCvbdbS3fdMOLTGUjt3Y9dwqJpUoGw3cEGGbXqnGDj0Y2hroecuIImMDihnJbtCXs2-Z_mcru2jv8v4cEyBuWYuOdbRRtIDyDJY1ck4w6iU5b9KzpkTvKeiT_p-C3lPQROiSQlF-vIzYeg_Dq-7y7QX4fAFMtmYekwnW5VdOUblj7B967JdP</recordid><startdate>20071101</startdate><enddate>20071101</enddate><creator>VERDEGUER, Francisco</creator><creator>CASTRO, Claudia</creator><creator>KUBICEK, Markus</creator><creator>PLA, Davinia</creator><creator>VILA-CABALLER, Marian</creator><creator>VINUE, Angela</creator><creator>CIVEIRA, Fernando</creator><creator>POCOVI, Miguel</creator><creator>CALVETE, Juan José</creator><creator>ANDRES, Vicente</creator><general>Oxford University Press</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20071101</creationdate><title>Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation</title><author>VERDEGUER, Francisco ; CASTRO, Claudia ; KUBICEK, Markus ; PLA, Davinia ; VILA-CABALLER, Marian ; VINUE, Angela ; CIVEIRA, Fernando ; POCOVI, Miguel ; CALVETE, Juan José ; ANDRES, Vicente</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c456t-c881bcb24d40a11f8f8b5c93796319d5a06c2b992cdbea14aeb543090f2e93a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Apolipoproteins E - physiology</topic><topic>Biological and medical sciences</topic><topic>Cardiology. Vascular system</topic><topic>Cell Proliferation</topic><topic>Complement C3 - physiology</topic><topic>Complement C3a - physiology</topic><topic>Complement System Proteins - physiology</topic><topic>Disorders of blood lipids. Hyperlipoproteinemia</topic><topic>Extracellular Signal-Regulated MAP Kinases - physiology</topic><topic>GTP-Binding Protein alpha Subunits, Gi-Go - physiology</topic><topic>Humans</topic><topic>Hypercholesterolemia - etiology</topic><topic>Macrophages - cytology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Molecular Sequence Data</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Myocytes, Smooth Muscle - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>VERDEGUER, Francisco</creatorcontrib><creatorcontrib>CASTRO, Claudia</creatorcontrib><creatorcontrib>KUBICEK, Markus</creatorcontrib><creatorcontrib>PLA, Davinia</creatorcontrib><creatorcontrib>VILA-CABALLER, Marian</creatorcontrib><creatorcontrib>VINUE, Angela</creatorcontrib><creatorcontrib>CIVEIRA, Fernando</creatorcontrib><creatorcontrib>POCOVI, Miguel</creatorcontrib><creatorcontrib>CALVETE, Juan José</creatorcontrib><creatorcontrib>ANDRES, Vicente</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>VERDEGUER, Francisco</au><au>CASTRO, Claudia</au><au>KUBICEK, Markus</au><au>PLA, Davinia</au><au>VILA-CABALLER, Marian</au><au>VINUE, Angela</au><au>CIVEIRA, Fernando</au><au>POCOVI, Miguel</au><au>CALVETE, Juan José</au><au>ANDRES, Vicente</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2007-11-01</date><risdate>2007</risdate><volume>76</volume><issue>2</issue><spage>340</spage><epage>350</epage><pages>340-350</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><coden>CVREAU</coden><abstract>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.
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.
Fat-fed apoE-KO mice experiencing severe hypercholesterolemia (approximately 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 manifested 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 gamma chain, C1s and C3c alpha 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 signal-regulated 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.
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.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>17673191</pmid><doi>10.1016/j.cardiores.2007.06.028</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Animals Apolipoproteins E - physiology Biological and medical sciences Cardiology. Vascular system Cell Proliferation Complement C3 - physiology Complement C3a - physiology Complement System Proteins - physiology Disorders of blood lipids. Hyperlipoproteinemia Extracellular Signal-Regulated MAP Kinases - physiology GTP-Binding Protein alpha Subunits, Gi-Go - physiology Humans Hypercholesterolemia - etiology Macrophages - cytology Male Medical sciences Metabolic diseases Mice Mice, Knockout Molecular Sequence Data Muscle, Smooth, Vascular - cytology Myocytes, Smooth Muscle - physiology |
| title | Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation |
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