Protein Kinase Cε-Calcineurin Cosignaling Downstream of Toll-Like Receptor 4 Downregulates Fibrosis and Induces Wound Healing Gene Expression in Cardiac Myofibroblasts

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Published in:	Molecular and Cellular Biology Vol. 34; no. 4; pp. 574 - 594
Main Authors:	Mesquita, Rui F. D. S., Paul, Margaret A., Valmaseda, Aida, Francois, Asvi, Jabr, Rita, Anjum, Shahzia, Marber, Michael S., Budhram-Mahadeo, Vishwanie, Heads, Richard J.
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 01-02-2014 Taylor & Francis
Subjects:	Animals Calcineurin - genetics Calcineurin - metabolism Cells, Cultured Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Fibrosis - genetics Fibrosis - metabolism Gene Expression Regulation Humans Mice Myocardium - metabolism Myofibroblasts - metabolism Protein Kinase C-epsilon - genetics Protein Kinase C-epsilon - metabolism Rats Toll-Like Receptor 4 - genetics Toll-Like Receptor 4 - metabolism Wound Healing - genetics Wound Healing - physiology
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Abstract	Classifications Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology. For an alternate route to MCB .asm.org, visit: MCB
AbstractList	The pathways which regulate resolution of inflammation and contribute to positive remodeling of the myocardium following injury are poorly understood. Here we show that protein kinase C epsilon (PKCε) cooperates with the phosphatase calcineurin (CN) to potentiate induction of cardioprotective gene expression while suppressing expression of fibrosis markers. This was achieved by detailed analysis of the regulation of cyclooxygenase 2 (COX-2) expression as a marker gene and by using gene expression profiling to identify genes regulated by coexpression of CN-Aα/PKCε in adult rat cardiac myofibroblasts (ARVFs) on a larger scale. GeneChip analysis of CN-Aα/PKCε-coexpressing ARVFs showed that COX-2 provides a signature for wound healing and is associated with downregulation of fibrosis markers, including connective tissue growth factor (CTGF), fibronectin, and collagens Col1a1, Col3a1, Col6a3, Col11a1, Col12a1, and Col14a1, with concomitant upregulation of cardioprotection markers, including COX-2 itself, lipocalin 2 (LCN2), tissue inhibitor of metalloproteinase 1 (TIMP-1), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). In primary rat cardiomyocyte cultures Toll-like receptor 4 (TLR4) agonist- or PKCε/CN-dependent COX-2 induction occurred in coresident fibroblasts and was blocked by selective inhibition of CN or PKC α/ε or elimination of fibroblasts. Furthermore, ectopic expression of PKCε and CN in ARVFs showed that the effects on COX-2 expression are mediated by specific NFAT sites within the COX-2 promoter as confirmed by site-directed mutagenesis and chromatin immunoprecipitation (ChIP). Therefore, PKCε may negatively regulate adverse myocardial remodeling by cooperating with CN to downregulate fibrosis and induce transcription of cardioprotective wound healing genes, including COX-2. The pathways which regulate resolution of inflammation and contribute to positive remodeling of the myocardium following injury are poorly understood. Here we show that protein kinase C epsilon (PKC epsilon ) cooperates with the phosphatase calcineurin (CN) to potentiate induction of cardioprotective gene expression while suppressing expression of fibrosis markers. This was achieved by detailed analysis of the regulation of cyclooxygenase 2 (COX-2) expression as a marker gene and by using gene expression profiling to identify genes regulated by coexpression of CN-A alpha /PKC epsilon in adult rat cardiac myofibroblasts (ARVFs) on a larger scale. GeneChip analysis of CN-A alpha /PKC epsilon -coexpressing ARVFs showed that COX-2 provides a signature for wound healing and is associated with downregulation of fibrosis markers, including connective tissue growth factor (CTGF), fibronectin, and collagens Col1a1, Col3a1, Col6a3, Col11a1, Col12a1, and Col14a1, with concomitant upregulation of cardioprotection markers, including COX-2 itself, lipocalin 2 (LCN2), tissue inhibitor of metalloproteinase 1 (TIMP-1), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). In primary rat cardiomyocyte cultures Toll-like receptor 4 (TLR4) agonist- or PKC epsilon /CN-dependent COX-2 induction occurred in coresident fibroblasts and was blocked by selective inhibition of CN or PKC alpha / epsilon or elimination of fibroblasts. Furthermore, ectopic expression of PKC epsilon and CN in ARVFs showed that the effects on COX-2 expression are mediated by specific NFAT sites within the COX-2 promoter as confirmed by site-directed mutagenesis and chromatin immunoprecipitation (ChIP). Therefore, PKC epsilon may negatively regulate adverse myocardial remodeling by cooperating with CN to downregulate fibrosis and induce transcription of cardioprotective wound healing genes, including COX-2. Classifications Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology. For an alternate route to MCB .asm.org, visit: MCB
Author	Shahzia Anjum Rui F. D. S. Mesquita Richard J. Heads Rita Jabr Margaret A. Paul Vishwanie Budhram-Mahadeo Aida Valmaseda Michael S. Marber Asvi Francois
Author_xml	– sequence: 1 givenname: Rui F. D. S. surname: Mesquita fullname: Mesquita, Rui F. D. S. organization: Cardiovascular Division, King's College London, Department of Cardiology, The Rayne Institute, St Thomas's Hospital – sequence: 2 givenname: Margaret A. surname: Paul fullname: Paul, Margaret A. organization: Cardiovascular Division, King's College London, Department of Cardiology, The Rayne Institute, St Thomas's Hospital – sequence: 3 givenname: Aida surname: Valmaseda fullname: Valmaseda, Aida organization: Faculty of Health and Life Sciences, Universitat Pompeu Fabra – sequence: 4 givenname: Asvi surname: Francois fullname: Francois, Asvi organization: Cardiovascular Division, King's College London, Department of Cardiology, The Rayne Institute, St Thomas's Hospital – sequence: 5 givenname: Rita surname: Jabr fullname: Jabr, Rita organization: Cardiovascular Division, King's College London, Department of Cardiology, The Rayne Institute, St Thomas's Hospital – sequence: 6 givenname: Shahzia surname: Anjum fullname: Anjum, Shahzia organization: Institute of Women's Health, UCL Cancer Institute, University College London – sequence: 7 givenname: Michael S. surname: Marber fullname: Marber, Michael S. organization: Cardiovascular Division, King's College London, Department of Cardiology, The Rayne Institute, St Thomas's Hospital – sequence: 8 givenname: Vishwanie surname: Budhram-Mahadeo fullname: Budhram-Mahadeo, Vishwanie organization: Medical Molecular Biology Unit, University College London – sequence: 9 givenname: Richard J. surname: Heads fullname: Heads, Richard J. email: richard.heads@kcl.ac.uk organization: Cardiovascular Division, King's College London, Department of Vascular Biology and Inflammation
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Rita Jabr, Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom. R.F.D.S.M. and M.A.P. contributed equally to this article.
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Snippet	Classifications Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit... The pathways which regulate resolution of inflammation and contribute to positive remodeling of the myocardium following injury are poorly understood. Here we...
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StartPage	574
SubjectTerms	Animals Calcineurin - genetics Calcineurin - metabolism Cells, Cultured Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Fibrosis - genetics Fibrosis - metabolism Gene Expression Regulation Humans Mice Myocardium - metabolism Myofibroblasts - metabolism Protein Kinase C-epsilon - genetics Protein Kinase C-epsilon - metabolism Rats Toll-Like Receptor 4 - genetics Toll-Like Receptor 4 - metabolism Wound Healing - genetics Wound Healing - physiology
Title	Protein Kinase Cε-Calcineurin Cosignaling Downstream of Toll-Like Receptor 4 Downregulates Fibrosis and Induces Wound Healing Gene Expression in Cardiac Myofibroblasts
URI	http://mcb.asm.org/content/34/4/574.abstract https://www.tandfonline.com/doi/abs/10.1128/MCB.01098-13 https://www.ncbi.nlm.nih.gov/pubmed/24298017 https://search.proquest.com/docview/1505342325 https://pubmed.ncbi.nlm.nih.gov/PMC3911483
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