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Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function
BACKGROUND: Hypercholesterolemia and low high density lipoprotein (HDL) cholesterol contribute to coronary heart disease but little is known about their direct effects on myocardial function. Low HDL and raised non-HDL cholesterol levels carried increased risk for heart failure development in the Fr...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464236/ https://www.ncbi.nlm.nih.gov/pubmed/23056485 http://dx.doi.org/10.1371/journal.pone.0046849 |
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author | Gordts, Stephanie C. Van Craeyveld, Eline Muthuramu, Ilayaraja Singh, Neha Jacobs, Frank De Geest, Bart |
author_facet | Gordts, Stephanie C. Van Craeyveld, Eline Muthuramu, Ilayaraja Singh, Neha Jacobs, Frank De Geest, Bart |
author_sort | Gordts, Stephanie C. |
collection | PubMed |
description | BACKGROUND: Hypercholesterolemia and low high density lipoprotein (HDL) cholesterol contribute to coronary heart disease but little is known about their direct effects on myocardial function. Low HDL and raised non-HDL cholesterol levels carried increased risk for heart failure development in the Framingham study, independent of any association with myocardial infarction. The objective of this study was to test the hypothesis that increased endothelial progenitor cell (EPC) number and function after lipid lowering or HDL raising gene transfer in C57BL/6 low density lipoprotein receptor deficient (LDLr(−/−)) mice may be associated with an enhanced relative vascularity in the myocardium and an improved cardiac function. METHODOLOGY/PRINCIPAL FINDINGS: Lipid lowering and HDL raising gene transfer were performed using the E1E3E4-deleted LDLr expressing adenoviral vector AdLDLr and the human apolipoprotein A-I expressing vector AdA-I, respectively. AdLDLr transfer in C57BL/6 LDLr(−/−) mice resulted in a 2.0-fold (p<0.05) increase of the circulating number of EPCs and in an improvement of EPC function as assessed by ex vivo EPC migration and EPC adhesion. Capillary density and relative vascularity in the myocardium were 28% (p<0.01) and 22% (p<0.05) higher, respectively, in AdLDLr mice compared to control mice. The peak rate of isovolumetric relaxation was increased by 12% (p<0.05) and the time constant of isovolumetric relaxation was decreased by 14% (p<0.05) after AdLDLr transfer. Similarly, HDL raising gene transfer increased EPC number and function and raised both capillary density and relative vascularity in the myocardium by 24% (p<0.05). The peak rate of isovolumetric relaxation was increased by 16% (p<0.05) in AdA-I mice compared to control mice. CONCLUSIONS/SIGNIFICANCE: Both lipid lowering and HDL raising gene transfer have beneficial effects on EPC biology, relative myocardial vascularity, and diastolic function. These findings raise concerns over the external validity of studies evaluating myocardial biology and cardiac repair in normocholesterolemic animals. |
format | Online Article Text |
id | pubmed-3464236 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34642362012-10-10 Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function Gordts, Stephanie C. Van Craeyveld, Eline Muthuramu, Ilayaraja Singh, Neha Jacobs, Frank De Geest, Bart PLoS One Research Article BACKGROUND: Hypercholesterolemia and low high density lipoprotein (HDL) cholesterol contribute to coronary heart disease but little is known about their direct effects on myocardial function. Low HDL and raised non-HDL cholesterol levels carried increased risk for heart failure development in the Framingham study, independent of any association with myocardial infarction. The objective of this study was to test the hypothesis that increased endothelial progenitor cell (EPC) number and function after lipid lowering or HDL raising gene transfer in C57BL/6 low density lipoprotein receptor deficient (LDLr(−/−)) mice may be associated with an enhanced relative vascularity in the myocardium and an improved cardiac function. METHODOLOGY/PRINCIPAL FINDINGS: Lipid lowering and HDL raising gene transfer were performed using the E1E3E4-deleted LDLr expressing adenoviral vector AdLDLr and the human apolipoprotein A-I expressing vector AdA-I, respectively. AdLDLr transfer in C57BL/6 LDLr(−/−) mice resulted in a 2.0-fold (p<0.05) increase of the circulating number of EPCs and in an improvement of EPC function as assessed by ex vivo EPC migration and EPC adhesion. Capillary density and relative vascularity in the myocardium were 28% (p<0.01) and 22% (p<0.05) higher, respectively, in AdLDLr mice compared to control mice. The peak rate of isovolumetric relaxation was increased by 12% (p<0.05) and the time constant of isovolumetric relaxation was decreased by 14% (p<0.05) after AdLDLr transfer. Similarly, HDL raising gene transfer increased EPC number and function and raised both capillary density and relative vascularity in the myocardium by 24% (p<0.05). The peak rate of isovolumetric relaxation was increased by 16% (p<0.05) in AdA-I mice compared to control mice. CONCLUSIONS/SIGNIFICANCE: Both lipid lowering and HDL raising gene transfer have beneficial effects on EPC biology, relative myocardial vascularity, and diastolic function. These findings raise concerns over the external validity of studies evaluating myocardial biology and cardiac repair in normocholesterolemic animals. Public Library of Science 2012-10-04 /pmc/articles/PMC3464236/ /pubmed/23056485 http://dx.doi.org/10.1371/journal.pone.0046849 Text en © 2012 Gordts 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Gordts, Stephanie C. Van Craeyveld, Eline Muthuramu, Ilayaraja Singh, Neha Jacobs, Frank De Geest, Bart Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function |
title | Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function |
title_full | Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function |
title_fullStr | Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function |
title_full_unstemmed | Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function |
title_short | Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function |
title_sort | lipid lowering and hdl raising gene transfer increase endothelial progenitor cells, enhance myocardial vascularity, and improve diastolic function |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464236/ https://www.ncbi.nlm.nih.gov/pubmed/23056485 http://dx.doi.org/10.1371/journal.pone.0046849 |
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