Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells
Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested (a) whether reactive oxygen species (ROS) and c-Src play roles in hypoxic induction of HIF-1alpha protein and PAI-1 gene expression in the rabbit aortic smooth muscle cell line C2/2 cells an...
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| Veröffentlicht in: | Cardiovascular research 2005-09, Vol.67 (4), p.714-722 |
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| creator | SATO, Hiroko SATO, Mahito KANAI, Hiroyoshi UCHIYAMA, Tsuyoshi ISO, Tatsuya OHYAMA, Yoshio SAKAMOTO, Hironosuke TAMURA, Junichi NAGAI, Ryozo KURABAYASHI, Masahiko |
| description | Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested (a) whether reactive oxygen species (ROS) and c-Src play roles in hypoxic induction of HIF-1alpha protein and PAI-1 gene expression in the rabbit aortic smooth muscle cell line C2/2 cells and primary cultures of rat aortic smooth muscle cells, and (b) how mitochondria act on the hypoxia-induced signaling mechanism.
Hypoxic exposure of C2/2 cells increased H2O2 generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression. Catalase, a scavenger of H2O2, inhibited the hypoxia-induced ROS generation and PAI-1 gene expression. Src kinase inhibitors PP1 and PP2 inhibited hypoxia-induced HIF-1alpha protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression.
Induction of HIF-1alpha protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1alpha protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature. |
| doi_str_mv | 10.1016/j.cardiores.2005.04.017 |
| format | Article |
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Hypoxic exposure of C2/2 cells increased H2O2 generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression. Catalase, a scavenger of H2O2, inhibited the hypoxia-induced ROS generation and PAI-1 gene expression. Src kinase inhibitors PP1 and PP2 inhibited hypoxia-induced HIF-1alpha protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression.
Induction of HIF-1alpha protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1alpha protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1016/j.cardiores.2005.04.017</identifier><identifier>PMID: 15913578</identifier><identifier>CODEN: CVREAU</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Androstadienes - pharmacology ; Animals ; Atherosclerosis (general aspects, experimental research) ; Biological and medical sciences ; Blood and lymphatic vessels ; Blotting, Northern ; Cardiology. Vascular system ; Catalase - pharmacology ; Cell Hypoxia ; Cell Line ; Flavonoids - pharmacology ; Hydrogen Peroxide - metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Imidazoles - pharmacology ; Immunoblotting ; Medical sciences ; Microscopy, Fluorescence ; Mitochondria - metabolism ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle - metabolism ; Naphthalenes - pharmacology ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphorylation ; Plasminogen Activator Inhibitor 1 - genetics ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins pp60(c-src) - metabolism ; Pyrazoles - pharmacology ; Pyridines - pharmacology ; Pyrimidines - pharmacology ; Rabbits ; RNA, Messenger - analysis ; Rotenone - pharmacology</subject><ispartof>Cardiovascular research, 2005-09, Vol.67 (4), p.714-722</ispartof><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-1ca513b46b1ef5704eeb5aa7142b79bf3c5444a7b3f0902ea0085a0fb7e391703</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16993252$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15913578$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SATO, Hiroko</creatorcontrib><creatorcontrib>SATO, Mahito</creatorcontrib><creatorcontrib>KANAI, Hiroyoshi</creatorcontrib><creatorcontrib>UCHIYAMA, Tsuyoshi</creatorcontrib><creatorcontrib>ISO, Tatsuya</creatorcontrib><creatorcontrib>OHYAMA, Yoshio</creatorcontrib><creatorcontrib>SAKAMOTO, Hironosuke</creatorcontrib><creatorcontrib>TAMURA, Junichi</creatorcontrib><creatorcontrib>NAGAI, Ryozo</creatorcontrib><creatorcontrib>KURABAYASHI, Masahiko</creatorcontrib><title>Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested (a) whether reactive oxygen species (ROS) and c-Src play roles in hypoxic induction of HIF-1alpha protein and PAI-1 gene expression in the rabbit aortic smooth muscle cell line C2/2 cells and primary cultures of rat aortic smooth muscle cells, and (b) how mitochondria act on the hypoxia-induced signaling mechanism.
Hypoxic exposure of C2/2 cells increased H2O2 generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression. Catalase, a scavenger of H2O2, inhibited the hypoxia-induced ROS generation and PAI-1 gene expression. Src kinase inhibitors PP1 and PP2 inhibited hypoxia-induced HIF-1alpha protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression.
Induction of HIF-1alpha protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1alpha protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature.</description><subject>Androstadienes - pharmacology</subject><subject>Animals</subject><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Blotting, Northern</subject><subject>Cardiology. Vascular system</subject><subject>Catalase - pharmacology</subject><subject>Cell Hypoxia</subject><subject>Cell Line</subject><subject>Flavonoids - pharmacology</subject><subject>Hydrogen Peroxide - metabolism</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>Imidazoles - pharmacology</subject><subject>Immunoblotting</subject><subject>Medical sciences</subject><subject>Microscopy, Fluorescence</subject><subject>Mitochondria - metabolism</subject><subject>Muscle, Smooth, Vascular</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Naphthalenes - pharmacology</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphorylation</subject><subject>Plasminogen Activator Inhibitor 1 - genetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins pp60(c-src) - metabolism</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridines - pharmacology</subject><subject>Pyrimidines - pharmacology</subject><subject>Rabbits</subject><subject>RNA, Messenger - analysis</subject><subject>Rotenone - pharmacology</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1v1DAQhi0EotvCXwBf4JYwju14c0QVX1IRB-BsTbwT1qskDp6k2v33ZOmqPY1m9Lwz9iPEWwWlAlV_OJQB8y6mTFxWALYEU4Jyz8RGOWsLXRn7XGwAYFvUutZX4pr5sLbWOvNSXCnbKG3ddiOO3-Ocwj6Nuxyxl5kwzPGeZDqe_tAoeaIQiSWOOxmKnznIqceTRBlynGM4J1JPMo5yf5rSMYZ1A09p5P-ze-Sw9JglDynNezksHFY6UN_zK_Giw57p9aXeiN-fP_26_Vrc_fjy7fbjXRF0A3OhAlqlW1O3ijrrwBC1FtEpU7WuaTsdrDEGXas7aKAiXL9sEbrWkW6UA30j3j_snXL6uxDPfoh8fgGOlBb29Ra2zlXVCroHMOTEnKnzU44D5pNX4M_S_cE_Svdn6R6MX6WvyTeXE0s70O4pd7G8Au8uwCoE-y7jGCI_cXXT6MpW-h8HSo_q</recordid><startdate>20050901</startdate><enddate>20050901</enddate><creator>SATO, Hiroko</creator><creator>SATO, Mahito</creator><creator>KANAI, Hiroyoshi</creator><creator>UCHIYAMA, Tsuyoshi</creator><creator>ISO, Tatsuya</creator><creator>OHYAMA, Yoshio</creator><creator>SAKAMOTO, Hironosuke</creator><creator>TAMURA, Junichi</creator><creator>NAGAI, Ryozo</creator><creator>KURABAYASHI, Masahiko</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>20050901</creationdate><title>Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells</title><author>SATO, Hiroko ; SATO, Mahito ; KANAI, Hiroyoshi ; UCHIYAMA, Tsuyoshi ; ISO, Tatsuya ; OHYAMA, Yoshio ; SAKAMOTO, Hironosuke ; TAMURA, Junichi ; NAGAI, Ryozo ; KURABAYASHI, Masahiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-1ca513b46b1ef5704eeb5aa7142b79bf3c5444a7b3f0902ea0085a0fb7e391703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Androstadienes - pharmacology</topic><topic>Animals</topic><topic>Atherosclerosis (general aspects, experimental research)</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Blotting, Northern</topic><topic>Cardiology. Vascular system</topic><topic>Catalase - pharmacology</topic><topic>Cell Hypoxia</topic><topic>Cell Line</topic><topic>Flavonoids - pharmacology</topic><topic>Hydrogen Peroxide - metabolism</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Imidazoles - pharmacology</topic><topic>Immunoblotting</topic><topic>Medical sciences</topic><topic>Microscopy, Fluorescence</topic><topic>Mitochondria - metabolism</topic><topic>Muscle, Smooth, Vascular</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Naphthalenes - pharmacology</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphorylation</topic><topic>Plasminogen Activator Inhibitor 1 - genetics</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins pp60(c-src) - metabolism</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyridines - pharmacology</topic><topic>Pyrimidines - pharmacology</topic><topic>Rabbits</topic><topic>RNA, Messenger - analysis</topic><topic>Rotenone - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SATO, Hiroko</creatorcontrib><creatorcontrib>SATO, Mahito</creatorcontrib><creatorcontrib>KANAI, Hiroyoshi</creatorcontrib><creatorcontrib>UCHIYAMA, Tsuyoshi</creatorcontrib><creatorcontrib>ISO, Tatsuya</creatorcontrib><creatorcontrib>OHYAMA, Yoshio</creatorcontrib><creatorcontrib>SAKAMOTO, Hironosuke</creatorcontrib><creatorcontrib>TAMURA, Junichi</creatorcontrib><creatorcontrib>NAGAI, Ryozo</creatorcontrib><creatorcontrib>KURABAYASHI, Masahiko</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>SATO, Hiroko</au><au>SATO, Mahito</au><au>KANAI, Hiroyoshi</au><au>UCHIYAMA, Tsuyoshi</au><au>ISO, Tatsuya</au><au>OHYAMA, Yoshio</au><au>SAKAMOTO, Hironosuke</au><au>TAMURA, Junichi</au><au>NAGAI, Ryozo</au><au>KURABAYASHI, Masahiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2005-09-01</date><risdate>2005</risdate><volume>67</volume><issue>4</issue><spage>714</spage><epage>722</epage><pages>714-722</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><coden>CVREAU</coden><abstract>Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested (a) whether reactive oxygen species (ROS) and c-Src play roles in hypoxic induction of HIF-1alpha protein and PAI-1 gene expression in the rabbit aortic smooth muscle cell line C2/2 cells and primary cultures of rat aortic smooth muscle cells, and (b) how mitochondria act on the hypoxia-induced signaling mechanism.
Hypoxic exposure of C2/2 cells increased H2O2 generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression. Catalase, a scavenger of H2O2, inhibited the hypoxia-induced ROS generation and PAI-1 gene expression. Src kinase inhibitors PP1 and PP2 inhibited hypoxia-induced HIF-1alpha protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression.
Induction of HIF-1alpha protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1alpha protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>15913578</pmid><doi>10.1016/j.cardiores.2005.04.017</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Androstadienes - pharmacology Animals Atherosclerosis (general aspects, experimental research) Biological and medical sciences Blood and lymphatic vessels Blotting, Northern Cardiology. Vascular system Catalase - pharmacology Cell Hypoxia Cell Line Flavonoids - pharmacology Hydrogen Peroxide - metabolism Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Imidazoles - pharmacology Immunoblotting Medical sciences Microscopy, Fluorescence Mitochondria - metabolism Muscle, Smooth, Vascular Myocytes, Smooth Muscle - metabolism Naphthalenes - pharmacology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphorylation Plasminogen Activator Inhibitor 1 - genetics Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins pp60(c-src) - metabolism Pyrazoles - pharmacology Pyridines - pharmacology Pyrimidines - pharmacology Rabbits RNA, Messenger - analysis Rotenone - pharmacology |
| title | Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells |
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