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Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia
OBJECTIVE: Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelium leads to arterial calcification in mice. The purpose of this study was to examine the effect of elevated endothelial TNAP on coronary atherosclerosis. In addition, we aimed to examine endogenous TNAP activity...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638543/ https://www.ncbi.nlm.nih.gov/pubmed/29023576 http://dx.doi.org/10.1371/journal.pone.0186426 |
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author | Romanelli, Filippo Corbo, AnthonyMarco Salehi, Maryam Yadav, Manisha C. Salman, Soha Petrosian, David Rashidbaigi, Omid J. Chait, Jesse Kuruvilla, Jes Plummer, Maria Radichev, Ilian Margulies, Kenneth B. Gerdes, A. Martin Pinkerton, Anthony B. Millán, José Luis Savinov, Alexei Y. Savinova, Olga V. |
author_facet | Romanelli, Filippo Corbo, AnthonyMarco Salehi, Maryam Yadav, Manisha C. Salman, Soha Petrosian, David Rashidbaigi, Omid J. Chait, Jesse Kuruvilla, Jes Plummer, Maria Radichev, Ilian Margulies, Kenneth B. Gerdes, A. Martin Pinkerton, Anthony B. Millán, José Luis Savinov, Alexei Y. Savinova, Olga V. |
author_sort | Romanelli, Filippo |
collection | PubMed |
description | OBJECTIVE: Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelium leads to arterial calcification in mice. The purpose of this study was to examine the effect of elevated endothelial TNAP on coronary atherosclerosis. In addition, we aimed to examine endogenous TNAP activity in human myocardium. APPROACH AND RESULTS: A vascular pattern of TNAP activity was observed in human non-failing, ischemic, and idiopathic dilated hearts (5 per group); no differences were noted between groups in this study. Endothelial overexpression of TNAP was achieved in mice harboring a homozygous recessive mutation in the low density lipoprotein receptor (whc allele) utilizing a Tie2-cre recombinase (WHC-eTNAP mice). WHC-eTNAP developed significant coronary artery calcification at baseline compared WHC controls (4312 vs 0μm(2) alizarin red area, p<0.001). Eight weeks after induction of atherosclerosis, lipid deposition in the coronary arteries of WHC-eTNAP was increased compared to WHC controls (121633 vs 9330μm(2) oil red O area, p<0.05). Coronary lesions in WHC-eTNAP mice exhibited intimal thickening, calcifications, foam cells, and necrotic cores. This was accompanied by the reduction in body weight and left ventricular ejection fraction (19.5 vs. 23.6g, p<0.01; 35% vs. 47%, p<0.05). In a placebo-controlled experiment under atherogenic conditions, pharmacological inhibition of TNAP in WHC-eTNAP mice by a specific inhibitor SBI-425 (30mg*kg(-1)*d(-1), for 5 weeks) reduced coronary calcium (78838 vs.144622μm(2)) and lipids (30754 vs. 77317μm(2)); improved body weight (22.4 vs.18.8g) and ejection fraction (59 vs. 47%). The effects of SBI-425 were significant in the direct comparisons with placebo but disappeared after TNAP-negative placebo-treated group was included in the models as healthy controls. CONCLUSIONS: Endogenous TNAP activity is present in human cardiac tissues. TNAP overexpression in vascular endothelium in mice leads to an unusual course of coronary atherosclerosis, in which calcification precedes lipid deposition. The prevalence and significance of this mechanism in human atherosclerosis requires further investigations. |
format | Online Article Text |
id | pubmed-5638543 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-56385432017-11-03 Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia Romanelli, Filippo Corbo, AnthonyMarco Salehi, Maryam Yadav, Manisha C. Salman, Soha Petrosian, David Rashidbaigi, Omid J. Chait, Jesse Kuruvilla, Jes Plummer, Maria Radichev, Ilian Margulies, Kenneth B. Gerdes, A. Martin Pinkerton, Anthony B. Millán, José Luis Savinov, Alexei Y. Savinova, Olga V. PLoS One Research Article OBJECTIVE: Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelium leads to arterial calcification in mice. The purpose of this study was to examine the effect of elevated endothelial TNAP on coronary atherosclerosis. In addition, we aimed to examine endogenous TNAP activity in human myocardium. APPROACH AND RESULTS: A vascular pattern of TNAP activity was observed in human non-failing, ischemic, and idiopathic dilated hearts (5 per group); no differences were noted between groups in this study. Endothelial overexpression of TNAP was achieved in mice harboring a homozygous recessive mutation in the low density lipoprotein receptor (whc allele) utilizing a Tie2-cre recombinase (WHC-eTNAP mice). WHC-eTNAP developed significant coronary artery calcification at baseline compared WHC controls (4312 vs 0μm(2) alizarin red area, p<0.001). Eight weeks after induction of atherosclerosis, lipid deposition in the coronary arteries of WHC-eTNAP was increased compared to WHC controls (121633 vs 9330μm(2) oil red O area, p<0.05). Coronary lesions in WHC-eTNAP mice exhibited intimal thickening, calcifications, foam cells, and necrotic cores. This was accompanied by the reduction in body weight and left ventricular ejection fraction (19.5 vs. 23.6g, p<0.01; 35% vs. 47%, p<0.05). In a placebo-controlled experiment under atherogenic conditions, pharmacological inhibition of TNAP in WHC-eTNAP mice by a specific inhibitor SBI-425 (30mg*kg(-1)*d(-1), for 5 weeks) reduced coronary calcium (78838 vs.144622μm(2)) and lipids (30754 vs. 77317μm(2)); improved body weight (22.4 vs.18.8g) and ejection fraction (59 vs. 47%). The effects of SBI-425 were significant in the direct comparisons with placebo but disappeared after TNAP-negative placebo-treated group was included in the models as healthy controls. CONCLUSIONS: Endogenous TNAP activity is present in human cardiac tissues. TNAP overexpression in vascular endothelium in mice leads to an unusual course of coronary atherosclerosis, in which calcification precedes lipid deposition. The prevalence and significance of this mechanism in human atherosclerosis requires further investigations. Public Library of Science 2017-10-12 /pmc/articles/PMC5638543/ /pubmed/29023576 http://dx.doi.org/10.1371/journal.pone.0186426 Text en © 2017 Romanelli et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Romanelli, Filippo Corbo, AnthonyMarco Salehi, Maryam Yadav, Manisha C. Salman, Soha Petrosian, David Rashidbaigi, Omid J. Chait, Jesse Kuruvilla, Jes Plummer, Maria Radichev, Ilian Margulies, Kenneth B. Gerdes, A. Martin Pinkerton, Anthony B. Millán, José Luis Savinov, Alexei Y. Savinova, Olga V. Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia |
title | Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia |
title_full | Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia |
title_fullStr | Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia |
title_full_unstemmed | Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia |
title_short | Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia |
title_sort | overexpression of tissue-nonspecific alkaline phosphatase (tnap) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638543/ https://www.ncbi.nlm.nih.gov/pubmed/29023576 http://dx.doi.org/10.1371/journal.pone.0186426 |
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