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Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet
Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in a...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122412/ https://www.ncbi.nlm.nih.gov/pubmed/25093405 http://dx.doi.org/10.1371/journal.pone.0104156 |
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author | Vecoli, Cecilia Novelli, Michela Pippa, Anna Giacopelli, Daniela Beffy, Pascale Masiello, Pellegrino L’Abbate, Antonio Neglia, Danilo |
author_facet | Vecoli, Cecilia Novelli, Michela Pippa, Anna Giacopelli, Daniela Beffy, Pascale Masiello, Pellegrino L’Abbate, Antonio Neglia, Danilo |
author_sort | Vecoli, Cecilia |
collection | PubMed |
description | Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT), eNOS(−/−) and eNOS(+/−) mice were studied. WT and eNOS(+/−) mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS(−/−). Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR) was measured at baseline and during infusions of acetylcholine (Ach) or sodium-nitroprusside (SNP) to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS(−/−)) showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS(−/−) and eNOS(+/−) mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS(−/−). The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary vessels, consistent with a shift towards a vasoconstrictive pattern. |
format | Online Article Text |
id | pubmed-4122412 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41224122014-08-12 Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet Vecoli, Cecilia Novelli, Michela Pippa, Anna Giacopelli, Daniela Beffy, Pascale Masiello, Pellegrino L’Abbate, Antonio Neglia, Danilo PLoS One Research Article Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT), eNOS(−/−) and eNOS(+/−) mice were studied. WT and eNOS(+/−) mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS(−/−). Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR) was measured at baseline and during infusions of acetylcholine (Ach) or sodium-nitroprusside (SNP) to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS(−/−)) showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS(−/−) and eNOS(+/−) mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS(−/−). The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary vessels, consistent with a shift towards a vasoconstrictive pattern. Public Library of Science 2014-08-05 /pmc/articles/PMC4122412/ /pubmed/25093405 http://dx.doi.org/10.1371/journal.pone.0104156 Text en © 2014 Vecoli 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 Vecoli, Cecilia Novelli, Michela Pippa, Anna Giacopelli, Daniela Beffy, Pascale Masiello, Pellegrino L’Abbate, Antonio Neglia, Danilo Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet |
title | Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet |
title_full | Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet |
title_fullStr | Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet |
title_full_unstemmed | Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet |
title_short | Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet |
title_sort | partial deletion of enos gene causes hyperinsulinemic state, unbalance of cardiac insulin signaling pathways and coronary dysfunction independently of high fat diet |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122412/ https://www.ncbi.nlm.nih.gov/pubmed/25093405 http://dx.doi.org/10.1371/journal.pone.0104156 |
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