Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein-1 release and structural remodelling of the lung in human and rodent chronic heart failure models
Introduction The burden of chronic heart failure (HF) is rising owing to an increased survivorship after myocardial infarction (MI). Pulmonary structural remodelling in patients with HF may protect against oedema while causing dyspnoea, the predominant symptom associated with HF. The cellular and mo...
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description | Introduction The burden of chronic heart failure (HF) is rising owing to an increased survivorship after myocardial infarction (MI). Pulmonary structural remodelling in patients with HF may protect against oedema while causing dyspnoea, the predominant symptom associated with HF. The cellular and molecular mechanisms underlying these processes in HF are poorly understood. We hypothesised that pulmonary venous hypertension (PVH) following MI provides a mechanical stimulus for structural remodelling of the lung via monocyte chemoattractant protein-1 (MCP-1). Methods Human lung microvascular endothelial cells (HLMVEC) and Ea.Hy 926 cells exposed to cyclic mechanical strain (CMS) in vitro were analysed for MCP-1 expression and activation of signalling intermediates. HF was induced in Sprague–Dawley rats 16 weeks after MI; a cohort was rescued with AAV9.SERCA2a gene therapy to reduce PVH. Results HLMVEC and Ea.Hy 926 cells exposed to CMS upregulated MCP-1 gene expression and protein release in an extracellular-signal-regulated kinase (ERK) 1/2 dependent manner. Supernatants from these experiments stimulated fibroblast (human fetal lung fibroblast -1) and pulmonary artery smooth muscle cell proliferation and differentiation. Total lung collagen, a marker of structural remodelling, and MCP-1 gene expression were increased in the lungs of rats with post-MI HF. SERCA2a gene therapy that attenuated PVH after MI was associated with lower levels of lung collagen and MCP-1 gene expression in the lung. Conclusions Mechanical strain associated with PVH may stimulate pulmonary structural remodelling through ERK 1/2 dependent induction of MCP-1. These findings provide insights into the pathophysiology of lung remodelling in HF and highlight novel, potential therapeutic targets. |
doi_str_mv | 10.1136/thoraxjnl-2013-204190 |
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Pulmonary structural remodelling in patients with HF may protect against oedema while causing dyspnoea, the predominant symptom associated with HF. The cellular and molecular mechanisms underlying these processes in HF are poorly understood. We hypothesised that pulmonary venous hypertension (PVH) following MI provides a mechanical stimulus for structural remodelling of the lung via monocyte chemoattractant protein-1 (MCP-1). Methods Human lung microvascular endothelial cells (HLMVEC) and Ea.Hy 926 cells exposed to cyclic mechanical strain (CMS) in vitro were analysed for MCP-1 expression and activation of signalling intermediates. HF was induced in Sprague–Dawley rats 16 weeks after MI; a cohort was rescued with AAV9.SERCA2a gene therapy to reduce PVH. Results HLMVEC and Ea.Hy 926 cells exposed to CMS upregulated MCP-1 gene expression and protein release in an extracellular-signal-regulated kinase (ERK) 1/2 dependent manner. Supernatants from these experiments stimulated fibroblast (human fetal lung fibroblast -1) and pulmonary artery smooth muscle cell proliferation and differentiation. Total lung collagen, a marker of structural remodelling, and MCP-1 gene expression were increased in the lungs of rats with post-MI HF. SERCA2a gene therapy that attenuated PVH after MI was associated with lower levels of lung collagen and MCP-1 gene expression in the lung. Conclusions Mechanical strain associated with PVH may stimulate pulmonary structural remodelling through ERK 1/2 dependent induction of MCP-1. These findings provide insights into the pathophysiology of lung remodelling in HF and highlight novel, potential therapeutic targets.</description><identifier>ISSN: 0040-6376</identifier><identifier>EISSN: 1468-3296</identifier><identifier>DOI: 10.1136/thoraxjnl-2013-204190</identifier><identifier>PMID: 25223582</identifier><identifier>CODEN: THORA7</identifier><language>eng</language><publisher>England: BMJ Publishing Group LTD</publisher><subject>Airway Remodeling - physiology ; Animals ; Cell Differentiation - drug effects ; Cell Proliferation - drug effects ; Cells, Cultured ; Chemokine CCL2 - biosynthesis ; Chemokine CCL2 - physiology ; Chemokines ; Collagen ; Culture Media, Conditioned - pharmacology ; Cytokines ; Disease Models, Animal ; Dyspnea ; Endothelial Cells - physiology ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - physiology ; Fibroblasts ; Fibroblasts - cytology ; Fibroblasts - drug effects ; Gene Expression Regulation - physiology ; Gene therapy ; Genetic Therapy - methods ; Heart failure ; Heart Failure - etiology ; Heart Failure - metabolism ; Heart Failure - physiopathology ; Humans ; Hypertension ; Hypertension, Pulmonary - etiology ; Hypertension, Pulmonary - metabolism ; Hypertension, Pulmonary - physiopathology ; Hypertension, Pulmonary - therapy ; Kinases ; Lungs ; Male ; MAP Kinase Signaling System - physiology ; Mechanotransduction, Cellular - physiology ; Myocardial Infarction - complications ; Penicillin ; Proteins ; Pulmonary arteries ; Rats, Sprague-Dawley ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics ; Smooth muscle ; Stress, Mechanical ; Tumor necrosis factor-TNF ; Up-Regulation - physiology</subject><ispartof>Thorax, 2014-12, Vol.69 (12), p.1120-1127</ispartof><rights>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</rights><rights>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</rights><rights>Copyright: 2014 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b425t-7c04351bcf3b9dcd0d91b8ea952357a79bca8e61c02d12f44bee70f0aeb812653</citedby><cites>FETCH-LOGICAL-b425t-7c04351bcf3b9dcd0d91b8ea952357a79bca8e61c02d12f44bee70f0aeb812653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://thorax.bmj.com/content/69/12/1120.full.pdf$$EPDF$$P50$$Gbmj$$H</linktopdf><linktohtml>$$Uhttps://thorax.bmj.com/content/69/12/1120.full$$EHTML$$P50$$Gbmj$$H</linktohtml><link.rule.ids>114,115,314,780,784,3196,23571,27924,27925,77600,77631</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25223582$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, John E S</creatorcontrib><creatorcontrib>Lyon, Alexander R</creatorcontrib><creatorcontrib>Shao, Dongmin</creatorcontrib><creatorcontrib>Hector, Lauren R</creatorcontrib><creatorcontrib>Xu, Hua</creatorcontrib><creatorcontrib>O'Gara, Peter</creatorcontrib><creatorcontrib>Pinhu, Liao</creatorcontrib><creatorcontrib>Chambers, Rachel C</creatorcontrib><creatorcontrib>Wort, S John</creatorcontrib><creatorcontrib>Griffiths, Mark J D</creatorcontrib><title>Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein-1 release and structural remodelling of the lung in human and rodent chronic heart failure models</title><title>Thorax</title><addtitle>Thorax</addtitle><description>Introduction The burden of chronic heart failure (HF) is rising owing to an increased survivorship after myocardial infarction (MI). Pulmonary structural remodelling in patients with HF may protect against oedema while causing dyspnoea, the predominant symptom associated with HF. The cellular and molecular mechanisms underlying these processes in HF are poorly understood. We hypothesised that pulmonary venous hypertension (PVH) following MI provides a mechanical stimulus for structural remodelling of the lung via monocyte chemoattractant protein-1 (MCP-1). Methods Human lung microvascular endothelial cells (HLMVEC) and Ea.Hy 926 cells exposed to cyclic mechanical strain (CMS) in vitro were analysed for MCP-1 expression and activation of signalling intermediates. HF was induced in Sprague–Dawley rats 16 weeks after MI; a cohort was rescued with AAV9.SERCA2a gene therapy to reduce PVH. Results HLMVEC and Ea.Hy 926 cells exposed to CMS upregulated MCP-1 gene expression and protein release in an extracellular-signal-regulated kinase (ERK) 1/2 dependent manner. Supernatants from these experiments stimulated fibroblast (human fetal lung fibroblast -1) and pulmonary artery smooth muscle cell proliferation and differentiation. Total lung collagen, a marker of structural remodelling, and MCP-1 gene expression were increased in the lungs of rats with post-MI HF. SERCA2a gene therapy that attenuated PVH after MI was associated with lower levels of lung collagen and MCP-1 gene expression in the lung. Conclusions Mechanical strain associated with PVH may stimulate pulmonary structural remodelling through ERK 1/2 dependent induction of MCP-1. These findings provide insights into the pathophysiology of lung remodelling in HF and highlight novel, potential therapeutic targets.</description><subject>Airway Remodeling - physiology</subject><subject>Animals</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Chemokine CCL2 - biosynthesis</subject><subject>Chemokine CCL2 - physiology</subject><subject>Chemokines</subject><subject>Collagen</subject><subject>Culture Media, Conditioned - pharmacology</subject><subject>Cytokines</subject><subject>Disease Models, Animal</subject><subject>Dyspnea</subject><subject>Endothelial Cells - physiology</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - physiology</subject><subject>Fibroblasts</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - drug effects</subject><subject>Gene Expression Regulation - physiology</subject><subject>Gene therapy</subject><subject>Genetic Therapy - methods</subject><subject>Heart failure</subject><subject>Heart Failure - etiology</subject><subject>Heart Failure - metabolism</subject><subject>Heart Failure - physiopathology</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Hypertension, Pulmonary - etiology</subject><subject>Hypertension, Pulmonary - metabolism</subject><subject>Hypertension, Pulmonary - physiopathology</subject><subject>Hypertension, Pulmonary - therapy</subject><subject>Kinases</subject><subject>Lungs</subject><subject>Male</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Mechanotransduction, Cellular - physiology</subject><subject>Myocardial Infarction - complications</subject><subject>Penicillin</subject><subject>Proteins</subject><subject>Pulmonary arteries</subject><subject>Rats, Sprague-Dawley</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics</subject><subject>Smooth muscle</subject><subject>Stress, Mechanical</subject><subject>Tumor necrosis factor-TNF</subject><subject>Up-Regulation - physiology</subject><issn>0040-6376</issn><issn>1468-3296</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqNkcuO1DAQRS0EYnoGPgFkiQ2bgB-JkyzRaGCQRoIFrKOKUyFpOXbjB6L_jk-jmh5mwYqNqySfe-2qy9gLKd5Iqc3bvIQIP_feVUpITUcte_GI7WRtukqr3jxmOyFqURndmgt2mdJeCNFJ2T5lF6pRSjed2rFfn4vbgod45D_Qh5L4cjxgzOjTGjwHP_EN7QJ-teB4yhFWT2XdioOMnKTBHqmxC24BMt3bDD7zQwwZV19JHtEhJPxjRfpic4lkFYmf0LnVf-Nh5nlB7gr1ZL-UDc5PR0LIzC4x0Af4ghAzn2F1JZ7eJn16xp7M4BI-v69X7Ov7my_Xt9Xdpw8fr9_dVWOtmly1VtS6kaOd9dhPdhJTL8cOoW9oES20_WihQyOtUJNUc12PiK2YBeDYSWUafcVen31psu8FUx62NVkaADzS2gZpVN1rpY0i9NU_6D6U6Ol3g2w72ZhetoKo5kzZGFKKOA-HuG4UxCDFcIp4eIh4OEU8nCMm3ct79zJuOD2o_mZKgDgD47b_T8_fb9q6Zg</recordid><startdate>201412</startdate><enddate>201412</enddate><creator>Park, John E S</creator><creator>Lyon, Alexander R</creator><creator>Shao, Dongmin</creator><creator>Hector, Lauren R</creator><creator>Xu, Hua</creator><creator>O'Gara, Peter</creator><creator>Pinhu, Liao</creator><creator>Chambers, Rachel C</creator><creator>Wort, S John</creator><creator>Griffiths, Mark J D</creator><general>BMJ Publishing Group LTD</general><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>201412</creationdate><title>Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein-1 release and structural remodelling of the lung in human and rodent chronic heart failure models</title><author>Park, John E S ; Lyon, Alexander R ; Shao, Dongmin ; Hector, Lauren R ; Xu, Hua ; O'Gara, Peter ; Pinhu, Liao ; Chambers, Rachel C ; Wort, S John ; Griffiths, Mark J D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b425t-7c04351bcf3b9dcd0d91b8ea952357a79bca8e61c02d12f44bee70f0aeb812653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Airway Remodeling - physiology</topic><topic>Animals</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Chemokine CCL2 - biosynthesis</topic><topic>Chemokine CCL2 - physiology</topic><topic>Chemokines</topic><topic>Collagen</topic><topic>Culture Media, Conditioned - pharmacology</topic><topic>Cytokines</topic><topic>Disease Models, Animal</topic><topic>Dyspnea</topic><topic>Endothelial Cells - physiology</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - physiology</topic><topic>Fibroblasts</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - drug effects</topic><topic>Gene Expression Regulation - physiology</topic><topic>Gene therapy</topic><topic>Genetic Therapy - methods</topic><topic>Heart failure</topic><topic>Heart Failure - etiology</topic><topic>Heart Failure - metabolism</topic><topic>Heart Failure - physiopathology</topic><topic>Humans</topic><topic>Hypertension</topic><topic>Hypertension, Pulmonary - etiology</topic><topic>Hypertension, Pulmonary - metabolism</topic><topic>Hypertension, Pulmonary - physiopathology</topic><topic>Hypertension, Pulmonary - therapy</topic><topic>Kinases</topic><topic>Lungs</topic><topic>Male</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mechanotransduction, Cellular - physiology</topic><topic>Myocardial Infarction - complications</topic><topic>Penicillin</topic><topic>Proteins</topic><topic>Pulmonary arteries</topic><topic>Rats, Sprague-Dawley</topic><topic>Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics</topic><topic>Smooth muscle</topic><topic>Stress, Mechanical</topic><topic>Tumor necrosis factor-TNF</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Park, John E S</creatorcontrib><creatorcontrib>Lyon, Alexander R</creatorcontrib><creatorcontrib>Shao, Dongmin</creatorcontrib><creatorcontrib>Hector, Lauren R</creatorcontrib><creatorcontrib>Xu, Hua</creatorcontrib><creatorcontrib>O'Gara, Peter</creatorcontrib><creatorcontrib>Pinhu, Liao</creatorcontrib><creatorcontrib>Chambers, Rachel C</creatorcontrib><creatorcontrib>Wort, S John</creatorcontrib><creatorcontrib>Griffiths, Mark J D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Thorax</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Park, John E S</au><au>Lyon, Alexander R</au><au>Shao, Dongmin</au><au>Hector, Lauren R</au><au>Xu, Hua</au><au>O'Gara, Peter</au><au>Pinhu, Liao</au><au>Chambers, Rachel C</au><au>Wort, S John</au><au>Griffiths, Mark J D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein-1 release and structural remodelling of the lung in human and rodent chronic heart failure models</atitle><jtitle>Thorax</jtitle><addtitle>Thorax</addtitle><date>2014-12</date><risdate>2014</risdate><volume>69</volume><issue>12</issue><spage>1120</spage><epage>1127</epage><pages>1120-1127</pages><issn>0040-6376</issn><eissn>1468-3296</eissn><coden>THORA7</coden><abstract>Introduction The burden of chronic heart failure (HF) is rising owing to an increased survivorship after myocardial infarction (MI). Pulmonary structural remodelling in patients with HF may protect against oedema while causing dyspnoea, the predominant symptom associated with HF. The cellular and molecular mechanisms underlying these processes in HF are poorly understood. We hypothesised that pulmonary venous hypertension (PVH) following MI provides a mechanical stimulus for structural remodelling of the lung via monocyte chemoattractant protein-1 (MCP-1). Methods Human lung microvascular endothelial cells (HLMVEC) and Ea.Hy 926 cells exposed to cyclic mechanical strain (CMS) in vitro were analysed for MCP-1 expression and activation of signalling intermediates. HF was induced in Sprague–Dawley rats 16 weeks after MI; a cohort was rescued with AAV9.SERCA2a gene therapy to reduce PVH. Results HLMVEC and Ea.Hy 926 cells exposed to CMS upregulated MCP-1 gene expression and protein release in an extracellular-signal-regulated kinase (ERK) 1/2 dependent manner. Supernatants from these experiments stimulated fibroblast (human fetal lung fibroblast -1) and pulmonary artery smooth muscle cell proliferation and differentiation. Total lung collagen, a marker of structural remodelling, and MCP-1 gene expression were increased in the lungs of rats with post-MI HF. SERCA2a gene therapy that attenuated PVH after MI was associated with lower levels of lung collagen and MCP-1 gene expression in the lung. Conclusions Mechanical strain associated with PVH may stimulate pulmonary structural remodelling through ERK 1/2 dependent induction of MCP-1. These findings provide insights into the pathophysiology of lung remodelling in HF and highlight novel, potential therapeutic targets.</abstract><cop>England</cop><pub>BMJ Publishing Group LTD</pub><pmid>25223582</pmid><doi>10.1136/thoraxjnl-2013-204190</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Airway Remodeling - physiology Animals Cell Differentiation - drug effects Cell Proliferation - drug effects Cells, Cultured Chemokine CCL2 - biosynthesis Chemokine CCL2 - physiology Chemokines Collagen Culture Media, Conditioned - pharmacology Cytokines Disease Models, Animal Dyspnea Endothelial Cells - physiology Endothelium, Vascular - metabolism Endothelium, Vascular - physiology Fibroblasts Fibroblasts - cytology Fibroblasts - drug effects Gene Expression Regulation - physiology Gene therapy Genetic Therapy - methods Heart failure Heart Failure - etiology Heart Failure - metabolism Heart Failure - physiopathology Humans Hypertension Hypertension, Pulmonary - etiology Hypertension, Pulmonary - metabolism Hypertension, Pulmonary - physiopathology Hypertension, Pulmonary - therapy Kinases Lungs Male MAP Kinase Signaling System - physiology Mechanotransduction, Cellular - physiology Myocardial Infarction - complications Penicillin Proteins Pulmonary arteries Rats, Sprague-Dawley Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics Smooth muscle Stress, Mechanical Tumor necrosis factor-TNF Up-Regulation - physiology |
title | Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein-1 release and structural remodelling of the lung in human and rodent chronic heart failure models |
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