PMID- 25223582 OWN - NLM STAT- MEDLINE DCOM- 20150112 LR - 20220129 IS - 1468-3296 (Electronic) IS - 0040-6376 (Linking) VI - 69 IP - 12 DP - 2014 Dec TI - 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. PG - 1120-7 LID - 10.1136/thoraxjnl-2013-204190 [doi] AB - 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. CI - 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. FAU - Park, John E S AU - Park JE AD - Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK. FAU - Lyon, Alexander R AU - Lyon AR AD - NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK Myocardial Function Unit, National Heart and Lung Institute, Imperial College, London, UK. FAU - Shao, Dongmin AU - Shao D AD - Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK. FAU - Hector, Lauren R AU - Hector LR AD - Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK. FAU - Xu, Hua AU - Xu H AD - NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK. FAU - O'Gara, Peter AU - O'Gara P AD - Myocardial Function Unit, National Heart and Lung Institute, Imperial College, London, UK. FAU - Pinhu, Liao AU - Pinhu L AD - Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK. FAU - Chambers, Rachel C AU - Chambers RC AD - Centre for Inflammation and Tissue Repair (CITR), University College London, Rayne Institute, London, UK. FAU - Wort, S John AU - Wort SJ AD - Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK. FAU - Griffiths, Mark J D AU - Griffiths MJ AD - Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK. LA - eng GR - FS/11/67/28954/BHF_/British Heart Foundation/United Kingdom GR - G0500373/MRC_/Medical Research Council/United Kingdom GR - G0701361/MRC_/Medical Research Council/United Kingdom GR - FS/11/67/2894/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140915 PL - England TA - Thorax JT - Thorax JID - 0417353 RN - 0 (Atp2a2 protein, rat) RN - 0 (CCL2 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Culture Media, Conditioned) RN - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases) SB - IM MH - Airway Remodeling/*physiology MH - Animals MH - Cell Differentiation/drug effects MH - Cell Proliferation/drug effects MH - Cells, Cultured MH - Chemokine CCL2/*biosynthesis/physiology MH - Culture Media, Conditioned/pharmacology MH - Disease Models, Animal MH - Endothelial Cells/physiology MH - Endothelium, Vascular/metabolism/physiology MH - Fibroblasts/cytology/drug effects MH - Gene Expression Regulation/physiology MH - Genetic Therapy/methods MH - Heart Failure/etiology/metabolism/*physiopathology MH - Humans MH - Hypertension, Pulmonary/etiology/*metabolism/physiopathology/therapy MH - MAP Kinase Signaling System/physiology MH - Male MH - Mechanotransduction, Cellular/*physiology MH - Myocardial Infarction/complications MH - Rats, Sprague-Dawley MH - Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics MH - Stress, Mechanical MH - Up-Regulation/physiology OTO - NOTNLM OT - Pulmonary oedema OT - Systemic disease and lungs EDAT- 2014/09/17 06:00 MHDA- 2015/01/13 06:00 CRDT- 2014/09/17 06:00 PHST- 2014/09/17 06:00 [entrez] PHST- 2014/09/17 06:00 [pubmed] PHST- 2015/01/13 06:00 [medline] AID - thoraxjnl-2013-204190 [pii] AID - 10.1136/thoraxjnl-2013-204190 [doi] PST - ppublish SO - Thorax. 2014 Dec;69(12):1120-7. doi: 10.1136/thoraxjnl-2013-204190. Epub 2014 Sep 15.