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Deamidated Lipocalin‐2 Induces Endothelial Dysfunction and Hypertension in Dietary Obese Mice
BACKGROUND: Lipocalin‐2 is a proinflammatory adipokine upregulated in obese humans and animals. A pathogenic role of lipocalin‐2 in hypertension has been suggested. Mice lacking lipocalin‐2 are protected from dietary obesity‐induced cardiovascular dysfunctions. Administration of lipocalin‐2 causes a...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187505/ https://www.ncbi.nlm.nih.gov/pubmed/24721803 http://dx.doi.org/10.1161/JAHA.114.000837 |
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author | Song, Erfei Fan, Pengcheng Huang, Bosheng Deng, Han‐Bing Cheung, Bernard Man Yung Félétou, Michel Vilaine, Jean‐Paul Villeneuve, Nicole Xu, Aimin Vanhoutte, Paul M. Wang, Yu |
author_facet | Song, Erfei Fan, Pengcheng Huang, Bosheng Deng, Han‐Bing Cheung, Bernard Man Yung Félétou, Michel Vilaine, Jean‐Paul Villeneuve, Nicole Xu, Aimin Vanhoutte, Paul M. Wang, Yu |
author_sort | Song, Erfei |
collection | PubMed |
description | BACKGROUND: Lipocalin‐2 is a proinflammatory adipokine upregulated in obese humans and animals. A pathogenic role of lipocalin‐2 in hypertension has been suggested. Mice lacking lipocalin‐2 are protected from dietary obesity‐induced cardiovascular dysfunctions. Administration of lipocalin‐2 causes abnormal vasodilator responses in mice on a high‐fat diet (HFD). METHODS AND RESULTS: Wild‐type and lipocalin‐2 knockout mice were fed with standard chow or HFD. Immunoassays were performed for evaluating the circulating and tissue contents of lipocalin‐2. The relaxation and contraction of arteries were studied using a wire myograph. Blood pressure was monitored with implantable radio telemetry. Dietary obesity promoted the accumulation of lipocalin‐2 protein in blood and arteries. Deficiency of this adipokine protected mice from dietary obesity‐induced elevation of blood pressure. Mass spectrometry analysis revealed that human and murine lipocalin‐2 were modified by polyamination. Polyaminated lipocalin‐2 was rapidly cleared from the circulation. Adipose tissue was a major site for lipocalin‐2 deamidation. The circulating levels and the arterial accumulation of deamidated lipocalin‐2 were significantly enhanced by treatment with linoleic acid (18:2n−6), which bound to lipocalin‐2 with high affinity and prevented its interactions with matrix metalloproteinase 9 (MMP9). Combined administration of linoleic acid with lipocalin‐2 caused vascular inflammation and endothelial dysfunction and raised the blood pressure of mice receiving standard chow. A human lipocalin‐2 mutant with cysteine 87 replaced by alanine (C87A) contained less polyamines and exhibited a reduced capacity to form heterodimeric complexes with MMP9. After treatment, C87A remained in the circulation for a prolonged period of time and evoked endothelial dysfunction in the absence of linoleic acid. CONCLUSIONS: Polyamination facilitates the clearance of lipocalin‐2, whereas the accumulation of deamidated lipocalin‐2 in arteries causes vascular inflammation, endothelial dysfunction, and hypertension. |
format | Online Article Text |
id | pubmed-4187505 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-41875052014-11-03 Deamidated Lipocalin‐2 Induces Endothelial Dysfunction and Hypertension in Dietary Obese Mice Song, Erfei Fan, Pengcheng Huang, Bosheng Deng, Han‐Bing Cheung, Bernard Man Yung Félétou, Michel Vilaine, Jean‐Paul Villeneuve, Nicole Xu, Aimin Vanhoutte, Paul M. Wang, Yu J Am Heart Assoc Original Research BACKGROUND: Lipocalin‐2 is a proinflammatory adipokine upregulated in obese humans and animals. A pathogenic role of lipocalin‐2 in hypertension has been suggested. Mice lacking lipocalin‐2 are protected from dietary obesity‐induced cardiovascular dysfunctions. Administration of lipocalin‐2 causes abnormal vasodilator responses in mice on a high‐fat diet (HFD). METHODS AND RESULTS: Wild‐type and lipocalin‐2 knockout mice were fed with standard chow or HFD. Immunoassays were performed for evaluating the circulating and tissue contents of lipocalin‐2. The relaxation and contraction of arteries were studied using a wire myograph. Blood pressure was monitored with implantable radio telemetry. Dietary obesity promoted the accumulation of lipocalin‐2 protein in blood and arteries. Deficiency of this adipokine protected mice from dietary obesity‐induced elevation of blood pressure. Mass spectrometry analysis revealed that human and murine lipocalin‐2 were modified by polyamination. Polyaminated lipocalin‐2 was rapidly cleared from the circulation. Adipose tissue was a major site for lipocalin‐2 deamidation. The circulating levels and the arterial accumulation of deamidated lipocalin‐2 were significantly enhanced by treatment with linoleic acid (18:2n−6), which bound to lipocalin‐2 with high affinity and prevented its interactions with matrix metalloproteinase 9 (MMP9). Combined administration of linoleic acid with lipocalin‐2 caused vascular inflammation and endothelial dysfunction and raised the blood pressure of mice receiving standard chow. A human lipocalin‐2 mutant with cysteine 87 replaced by alanine (C87A) contained less polyamines and exhibited a reduced capacity to form heterodimeric complexes with MMP9. After treatment, C87A remained in the circulation for a prolonged period of time and evoked endothelial dysfunction in the absence of linoleic acid. CONCLUSIONS: Polyamination facilitates the clearance of lipocalin‐2, whereas the accumulation of deamidated lipocalin‐2 in arteries causes vascular inflammation, endothelial dysfunction, and hypertension. Blackwell Publishing Ltd 2014-04-25 /pmc/articles/PMC4187505/ /pubmed/24721803 http://dx.doi.org/10.1161/JAHA.114.000837 Text en © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/3.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Research Song, Erfei Fan, Pengcheng Huang, Bosheng Deng, Han‐Bing Cheung, Bernard Man Yung Félétou, Michel Vilaine, Jean‐Paul Villeneuve, Nicole Xu, Aimin Vanhoutte, Paul M. Wang, Yu Deamidated Lipocalin‐2 Induces Endothelial Dysfunction and Hypertension in Dietary Obese Mice |
title | Deamidated Lipocalin‐2 Induces Endothelial Dysfunction and Hypertension in Dietary Obese Mice |
title_full | Deamidated Lipocalin‐2 Induces Endothelial Dysfunction and Hypertension in Dietary Obese Mice |
title_fullStr | Deamidated Lipocalin‐2 Induces Endothelial Dysfunction and Hypertension in Dietary Obese Mice |
title_full_unstemmed | Deamidated Lipocalin‐2 Induces Endothelial Dysfunction and Hypertension in Dietary Obese Mice |
title_short | Deamidated Lipocalin‐2 Induces Endothelial Dysfunction and Hypertension in Dietary Obese Mice |
title_sort | deamidated lipocalin‐2 induces endothelial dysfunction and hypertension in dietary obese mice |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187505/ https://www.ncbi.nlm.nih.gov/pubmed/24721803 http://dx.doi.org/10.1161/JAHA.114.000837 |
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