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Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia
The role of p38 mitogen-activated protein kinase (MAPK) activation in lipopolysaccharide (LPS)-induced myocardial dysfunction has not been clearly defined. Our aim was to investigate the contribution of p38 MAPK in myocardial tumor necrosis factor-alpha (TNF-alpha) expression, cardiac function and s...
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| Published in: | Cardiovascular research 2003-10, Vol.59 (4), p.893-900 |
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| container_end_page | 900 |
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| container_title | Cardiovascular research |
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| creator | TIANQING PENG XIANGRU LU MING LEI MOE, Gordon W QINGPING FENG |
| description | The role of p38 mitogen-activated protein kinase (MAPK) activation in lipopolysaccharide (LPS)-induced myocardial dysfunction has not been clearly defined. Our aim was to investigate the contribution of p38 MAPK in myocardial tumor necrosis factor-alpha (TNF-alpha) expression, cardiac function and survival during acute endotoxemia in mice.
Acute endotoxemia was induced by LPS (10 mg/kg, i.p.) in mice. Two hours after LPS treatment, left ventricular (LV) function was assessed. Phosphorylation of p38 MAPK was measured by Western blotting. TNF-alpha mRNA and protein levels were determined by semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.
LPS rapidly increased phosphorylation of p38 MAPK, followed by TNF-alpha mRNA expression and protein expression in the LV myocardium. Pre-treatment of the p38 MAPK inhibitor SB202190 (2 mg/kg, i.p.) decreased TNF-alpha mRNA and protein by 65 and 36%, respectively (P |
| doi_str_mv | 10.1016/s0008-6363(03)00509-1 |
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Acute endotoxemia was induced by LPS (10 mg/kg, i.p.) in mice. Two hours after LPS treatment, left ventricular (LV) function was assessed. Phosphorylation of p38 MAPK was measured by Western blotting. TNF-alpha mRNA and protein levels were determined by semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.
LPS rapidly increased phosphorylation of p38 MAPK, followed by TNF-alpha mRNA expression and protein expression in the LV myocardium. Pre-treatment of the p38 MAPK inhibitor SB202190 (2 mg/kg, i.p.) decreased TNF-alpha mRNA and protein by 65 and 36%, respectively (P<0.05). Immunohistochemical staining confirmed that cardiomyocytes were the major source of TNF-alpha production in the myocardium and blocking p38 MAPK activation inhibited TNF-alpha expression in response to LPS. Pre-treatment of SB202190 or a TNF-alpha antagonist etanercept (2 mg/kg, i.p) significantly reversed LPS-induced LV depression (P<0.05). LPS (20 mg/kg, i.p.) induced 94% mortality in mice within 72 h and pre-treatment with SB202190 and etanercept decreased LPS-induced mortality to 65 and 40%, respectively (P<0.01).
p38 MAPK activation represents an important mechanism leading to myocardial TNF-alpha production and cardiac dysfunction during acute endotoxemia in mice. Our data suggest that p38 MAPK is a potential therapeutic target of endotoxemia.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1016/s0008-6363(03)00509-1</identifier><identifier>PMID: 14553829</identifier><identifier>CODEN: CVREAU</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Acute Disease ; Animals ; Bacterial diseases ; Biological and medical sciences ; Endotoxemia - metabolism ; Etanercept ; General aspects ; Imidazoles - pharmacology ; Immunoglobulin G - pharmacology ; Immunologic Factors - pharmacology ; Infectious diseases ; Lipopolysaccharides ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinases - metabolism ; Myocardium - metabolism ; p38 Mitogen-Activated Protein Kinases ; Phosphorylation ; Pyridines - pharmacology ; Receptors, Tumor Necrosis Factor ; Reverse Transcriptase Polymerase Chain Reaction ; RNA - analysis ; Signal Transduction ; Tumor Necrosis Factor-alpha - analysis ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - metabolism ; Ventricular Dysfunction, Left</subject><ispartof>Cardiovascular research, 2003-10, Vol.59 (4), p.893-900</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c401t-525bc79a493578ce628ea9a220a504a21c9b4fe016f2b8d651ff370854f1f83c3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27922,27923</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15193000$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14553829$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>TIANQING PENG</creatorcontrib><creatorcontrib>XIANGRU LU</creatorcontrib><creatorcontrib>MING LEI</creatorcontrib><creatorcontrib>MOE, Gordon W</creatorcontrib><creatorcontrib>QINGPING FENG</creatorcontrib><title>Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>The role of p38 mitogen-activated protein kinase (MAPK) activation in lipopolysaccharide (LPS)-induced myocardial dysfunction has not been clearly defined. Our aim was to investigate the contribution of p38 MAPK in myocardial tumor necrosis factor-alpha (TNF-alpha) expression, cardiac function and survival during acute endotoxemia in mice.
Acute endotoxemia was induced by LPS (10 mg/kg, i.p.) in mice. Two hours after LPS treatment, left ventricular (LV) function was assessed. Phosphorylation of p38 MAPK was measured by Western blotting. TNF-alpha mRNA and protein levels were determined by semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.
LPS rapidly increased phosphorylation of p38 MAPK, followed by TNF-alpha mRNA expression and protein expression in the LV myocardium. Pre-treatment of the p38 MAPK inhibitor SB202190 (2 mg/kg, i.p.) decreased TNF-alpha mRNA and protein by 65 and 36%, respectively (P<0.05). Immunohistochemical staining confirmed that cardiomyocytes were the major source of TNF-alpha production in the myocardium and blocking p38 MAPK activation inhibited TNF-alpha expression in response to LPS. Pre-treatment of SB202190 or a TNF-alpha antagonist etanercept (2 mg/kg, i.p) significantly reversed LPS-induced LV depression (P<0.05). LPS (20 mg/kg, i.p.) induced 94% mortality in mice within 72 h and pre-treatment with SB202190 and etanercept decreased LPS-induced mortality to 65 and 40%, respectively (P<0.01).
p38 MAPK activation represents an important mechanism leading to myocardial TNF-alpha production and cardiac dysfunction during acute endotoxemia in mice. Our data suggest that p38 MAPK is a potential therapeutic target of endotoxemia.</description><subject>Acute Disease</subject><subject>Animals</subject><subject>Bacterial diseases</subject><subject>Biological and medical sciences</subject><subject>Endotoxemia - metabolism</subject><subject>Etanercept</subject><subject>General aspects</subject><subject>Imidazoles - pharmacology</subject><subject>Immunoglobulin G - pharmacology</subject><subject>Immunologic Factors - pharmacology</subject><subject>Infectious diseases</subject><subject>Lipopolysaccharides</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Myocardium - metabolism</subject><subject>p38 Mitogen-Activated Protein Kinases</subject><subject>Phosphorylation</subject><subject>Pyridines - pharmacology</subject><subject>Receptors, Tumor Necrosis Factor</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA - analysis</subject><subject>Signal Transduction</subject><subject>Tumor Necrosis Factor-alpha - analysis</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Ventricular Dysfunction, Left</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><recordid>eNpVkMlKxTAUhoMoeh0eQclG0UU1Q0-H5UWccAR1HU7TBCOdTNqLLnx3W7wqQiAkfP9_Dh8hu5wdc8aTk8AYy6JEJvKQySPGgOURXyEzngJEUsSwSma_yAbZDOF1fAKk8TrZ4DGAzEQ-I59XzYsrXO_ahraWdjKjt_OHa1oa7Q0GE2j90Wr0pcOKPt2dR1h1L0jNe-dNCFMKm5K6uvPt4j9sh0b3P0AY_MItxl_XUNOUbd--m9rhNlmzWAWzs7y3yPP52dPpZXRzf3F1Or-JdMx4H4GAQqc5xrmENNMmEZnBHIVgCCxGwXVexNaMWqwosjIBbq1MWQax5TaTWm6Rg-_ecc23wYRe1S5oU1XYmHYIKoU0EVzyEYRvUPs2BG-s6ryr0X8oztTkXT1OUtUkVbHxTN7VlNtbDhiK2pR_qaXoEdhfAhg0VtZjo13444DncmyWX_k6jCc</recordid><startdate>20031001</startdate><enddate>20031001</enddate><creator>TIANQING PENG</creator><creator>XIANGRU LU</creator><creator>MING LEI</creator><creator>MOE, Gordon W</creator><creator>QINGPING FENG</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>20031001</creationdate><title>Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia</title><author>TIANQING PENG ; XIANGRU LU ; MING LEI ; MOE, Gordon W ; QINGPING FENG</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c401t-525bc79a493578ce628ea9a220a504a21c9b4fe016f2b8d651ff370854f1f83c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Acute Disease</topic><topic>Animals</topic><topic>Bacterial diseases</topic><topic>Biological and medical sciences</topic><topic>Endotoxemia - metabolism</topic><topic>Etanercept</topic><topic>General aspects</topic><topic>Imidazoles - pharmacology</topic><topic>Immunoglobulin G - pharmacology</topic><topic>Immunologic Factors - pharmacology</topic><topic>Infectious diseases</topic><topic>Lipopolysaccharides</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Myocardium - metabolism</topic><topic>p38 Mitogen-Activated Protein Kinases</topic><topic>Phosphorylation</topic><topic>Pyridines - pharmacology</topic><topic>Receptors, Tumor Necrosis Factor</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA - analysis</topic><topic>Signal Transduction</topic><topic>Tumor Necrosis Factor-alpha - analysis</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Ventricular Dysfunction, Left</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>TIANQING PENG</creatorcontrib><creatorcontrib>XIANGRU LU</creatorcontrib><creatorcontrib>MING LEI</creatorcontrib><creatorcontrib>MOE, Gordon W</creatorcontrib><creatorcontrib>QINGPING FENG</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>TIANQING PENG</au><au>XIANGRU LU</au><au>MING LEI</au><au>MOE, Gordon W</au><au>QINGPING FENG</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2003-10-01</date><risdate>2003</risdate><volume>59</volume><issue>4</issue><spage>893</spage><epage>900</epage><pages>893-900</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><coden>CVREAU</coden><abstract>The role of p38 mitogen-activated protein kinase (MAPK) activation in lipopolysaccharide (LPS)-induced myocardial dysfunction has not been clearly defined. Our aim was to investigate the contribution of p38 MAPK in myocardial tumor necrosis factor-alpha (TNF-alpha) expression, cardiac function and survival during acute endotoxemia in mice.
Acute endotoxemia was induced by LPS (10 mg/kg, i.p.) in mice. Two hours after LPS treatment, left ventricular (LV) function was assessed. Phosphorylation of p38 MAPK was measured by Western blotting. TNF-alpha mRNA and protein levels were determined by semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.
LPS rapidly increased phosphorylation of p38 MAPK, followed by TNF-alpha mRNA expression and protein expression in the LV myocardium. Pre-treatment of the p38 MAPK inhibitor SB202190 (2 mg/kg, i.p.) decreased TNF-alpha mRNA and protein by 65 and 36%, respectively (P<0.05). Immunohistochemical staining confirmed that cardiomyocytes were the major source of TNF-alpha production in the myocardium and blocking p38 MAPK activation inhibited TNF-alpha expression in response to LPS. Pre-treatment of SB202190 or a TNF-alpha antagonist etanercept (2 mg/kg, i.p) significantly reversed LPS-induced LV depression (P<0.05). LPS (20 mg/kg, i.p.) induced 94% mortality in mice within 72 h and pre-treatment with SB202190 and etanercept decreased LPS-induced mortality to 65 and 40%, respectively (P<0.01).
p38 MAPK activation represents an important mechanism leading to myocardial TNF-alpha production and cardiac dysfunction during acute endotoxemia in mice. Our data suggest that p38 MAPK is a potential therapeutic target of endotoxemia.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>14553829</pmid><doi>10.1016/s0008-6363(03)00509-1</doi><tpages>8</tpages></addata></record> |
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| ispartof | Cardiovascular research, 2003-10, Vol.59 (4), p.893-900 |
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| source | Oxford Journals Online |
| subjects | Acute Disease Animals Bacterial diseases Biological and medical sciences Endotoxemia - metabolism Etanercept General aspects Imidazoles - pharmacology Immunoglobulin G - pharmacology Immunologic Factors - pharmacology Infectious diseases Lipopolysaccharides Male Medical sciences Mice Mice, Inbred C57BL Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - metabolism Myocardium - metabolism p38 Mitogen-Activated Protein Kinases Phosphorylation Pyridines - pharmacology Receptors, Tumor Necrosis Factor Reverse Transcriptase Polymerase Chain Reaction RNA - analysis Signal Transduction Tumor Necrosis Factor-alpha - analysis Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism Ventricular Dysfunction, Left |
| title | Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia |
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