Cargando…
Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1
BACKGROUND AND AIMS: Coronary artery disease (CAD) risk is associated with non-coding genetic variants at the phosphatase and actin regulating protein 1(PHACTR1) gene locus. The PHACTR1 gene encodes an actin-binding protein with phosphatase regulating activity. The mechanism whereby PHACTR1 influenc...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917897/ https://www.ncbi.nlm.nih.gov/pubmed/27187934 http://dx.doi.org/10.1016/j.atherosclerosis.2016.04.025 |
_version_ | 1782439016992342016 |
---|---|
author | Reschen, Michael E. Lin, Da Chalisey, Anil Soilleux, Elizabeth J. O’Callaghan, Christopher A. |
author_facet | Reschen, Michael E. Lin, Da Chalisey, Anil Soilleux, Elizabeth J. O’Callaghan, Christopher A. |
author_sort | Reschen, Michael E. |
collection | PubMed |
description | BACKGROUND AND AIMS: Coronary artery disease (CAD) risk is associated with non-coding genetic variants at the phosphatase and actin regulating protein 1(PHACTR1) gene locus. The PHACTR1 gene encodes an actin-binding protein with phosphatase regulating activity. The mechanism whereby PHACTR1 influences CAD risk is unknown. We hypothesized that PHACTR1 would be expressed in human cell types relevant to CAD and regulated by atherogenic or genetic factors. METHODS AND RESULTS: Using immunohistochemistry, we demonstrate that PHACTR1 protein is expressed strongly in human atherosclerotic plaque macrophages, lipid-laden foam cells, adventitial lymphocytes and endothelial cells. Using a combination of genomic analysis and molecular techniques, we demonstrate that PHACTR1 is expressed as multiple previously uncharacterized transcripts in macrophages, foam cells, lymphocytes and endothelial cells. Immunoblotting confirmed a total absence of PHACTR1 in vascular smooth muscle cells. Real-time quantitative PCR showed that PHACTR1 is regulated by atherogenic and inflammatory stimuli. In aortic endothelial cells, oxLDL and TNF-alpha both upregulated an intermediate length transcript. A short transcript expressed only in immune cells was upregulated in macrophages by oxidized low-density lipoprotein, and oxidized phospholipids but suppressed by lipopolysaccharide or TNF-alpha. In primary human macrophages, we identified a novel expression quantitative trait locus (eQTL) specific for this short transcript, whereby the risk allele at CAD risk SNP rs9349379 is associated with reduced PHACTR1 expression, similar to the effect of an inflammatory stimulus. CONCLUSIONS: Our data demonstrate that PHACTR1 is a key atherosclerosis candidate gene since it is regulated by atherogenic stimuli in macrophages and endothelial cells and we identify an effect of the genetic risk variant on PHACTR1 expression in macrophages that is similar to that of an inflammatory stimulus. |
format | Online Article Text |
id | pubmed-4917897 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-49178972016-07-01 Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1 Reschen, Michael E. Lin, Da Chalisey, Anil Soilleux, Elizabeth J. O’Callaghan, Christopher A. Atherosclerosis Article BACKGROUND AND AIMS: Coronary artery disease (CAD) risk is associated with non-coding genetic variants at the phosphatase and actin regulating protein 1(PHACTR1) gene locus. The PHACTR1 gene encodes an actin-binding protein with phosphatase regulating activity. The mechanism whereby PHACTR1 influences CAD risk is unknown. We hypothesized that PHACTR1 would be expressed in human cell types relevant to CAD and regulated by atherogenic or genetic factors. METHODS AND RESULTS: Using immunohistochemistry, we demonstrate that PHACTR1 protein is expressed strongly in human atherosclerotic plaque macrophages, lipid-laden foam cells, adventitial lymphocytes and endothelial cells. Using a combination of genomic analysis and molecular techniques, we demonstrate that PHACTR1 is expressed as multiple previously uncharacterized transcripts in macrophages, foam cells, lymphocytes and endothelial cells. Immunoblotting confirmed a total absence of PHACTR1 in vascular smooth muscle cells. Real-time quantitative PCR showed that PHACTR1 is regulated by atherogenic and inflammatory stimuli. In aortic endothelial cells, oxLDL and TNF-alpha both upregulated an intermediate length transcript. A short transcript expressed only in immune cells was upregulated in macrophages by oxidized low-density lipoprotein, and oxidized phospholipids but suppressed by lipopolysaccharide or TNF-alpha. In primary human macrophages, we identified a novel expression quantitative trait locus (eQTL) specific for this short transcript, whereby the risk allele at CAD risk SNP rs9349379 is associated with reduced PHACTR1 expression, similar to the effect of an inflammatory stimulus. CONCLUSIONS: Our data demonstrate that PHACTR1 is a key atherosclerosis candidate gene since it is regulated by atherogenic stimuli in macrophages and endothelial cells and we identify an effect of the genetic risk variant on PHACTR1 expression in macrophages that is similar to that of an inflammatory stimulus. Elsevier 2016-07 /pmc/articles/PMC4917897/ /pubmed/27187934 http://dx.doi.org/10.1016/j.atherosclerosis.2016.04.025 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Reschen, Michael E. Lin, Da Chalisey, Anil Soilleux, Elizabeth J. O’Callaghan, Christopher A. Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1 |
title | Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1 |
title_full | Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1 |
title_fullStr | Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1 |
title_full_unstemmed | Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1 |
title_short | Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1 |
title_sort | genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene phactr1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917897/ https://www.ncbi.nlm.nih.gov/pubmed/27187934 http://dx.doi.org/10.1016/j.atherosclerosis.2016.04.025 |
work_keys_str_mv | AT reschenmichaele geneticandenvironmentalriskfactorsforatherosclerosisregulatetranscriptionofphosphataseandactinregulatinggenephactr1 AT linda geneticandenvironmentalriskfactorsforatherosclerosisregulatetranscriptionofphosphataseandactinregulatinggenephactr1 AT chaliseyanil geneticandenvironmentalriskfactorsforatherosclerosisregulatetranscriptionofphosphataseandactinregulatinggenephactr1 AT soilleuxelizabethj geneticandenvironmentalriskfactorsforatherosclerosisregulatetranscriptionofphosphataseandactinregulatinggenephactr1 AT ocallaghanchristophera geneticandenvironmentalriskfactorsforatherosclerosisregulatetranscriptionofphosphataseandactinregulatinggenephactr1 |