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Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability

BACKGROUND: Diabetes is known to accelerate atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis mouse model, which reflects plaque instability/rupture...

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Autores principales: Chen, Yung‐Chih, Jandeleit‐Dahm, Karin, Peter, Karlheinz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075188/
https://www.ncbi.nlm.nih.gov/pubmed/34970931
http://dx.doi.org/10.1161/JAHA.121.022761
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author Chen, Yung‐Chih
Jandeleit‐Dahm, Karin
Peter, Karlheinz
author_facet Chen, Yung‐Chih
Jandeleit‐Dahm, Karin
Peter, Karlheinz
author_sort Chen, Yung‐Chih
collection PubMed
description BACKGROUND: Diabetes is known to accelerate atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis mouse model, which reflects plaque instability/rupture as seen in patients, can be applied to study the effects of diabetes and respective therapeutics on plaque instability/rupture. METHODS AND RESULTS: ApoE(−/−) mice at 7 weeks of age were rendered diabetic with streptozotocin and 5 weeks later were surgically subjected to tandem stenosis in the right carotid artery and fed with a high‐fat diet for 7 weeks. As a promising new antidiabetic drug class, a sodium glucose co‐transporter 2 inhibitor was tested in this new model. Diabetic mice showed an increase in the size of unstable atherosclerotic plaques and in the plaque instability markers MCP‐1, CD68, and necrotic core size. Mice treated with dapagliflozin demonstrated attenuated glucose and triglyceride levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap‐to‐lesion height ratios, and significant upregulation of the vasculoprotective NADPH oxidase 4 expression. CONCLUSIONS: The tandem stenosis mouse model in combination with the application of streptozotocin represents a highly suitable and unique mouse model for studying plaque destabilization under diabetic conditions. Furthermore, for the first time, we provide evidence of plaque‐stabilizing effects of sodium‐glucose co‐transporter 2 inhibitor. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing antidiabetic drugs for the highly sought‐after potential to stabilize atherosclerotic plaques.
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spelling pubmed-90751882022-05-10 Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability Chen, Yung‐Chih Jandeleit‐Dahm, Karin Peter, Karlheinz J Am Heart Assoc Brief Communication BACKGROUND: Diabetes is known to accelerate atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis mouse model, which reflects plaque instability/rupture as seen in patients, can be applied to study the effects of diabetes and respective therapeutics on plaque instability/rupture. METHODS AND RESULTS: ApoE(−/−) mice at 7 weeks of age were rendered diabetic with streptozotocin and 5 weeks later were surgically subjected to tandem stenosis in the right carotid artery and fed with a high‐fat diet for 7 weeks. As a promising new antidiabetic drug class, a sodium glucose co‐transporter 2 inhibitor was tested in this new model. Diabetic mice showed an increase in the size of unstable atherosclerotic plaques and in the plaque instability markers MCP‐1, CD68, and necrotic core size. Mice treated with dapagliflozin demonstrated attenuated glucose and triglyceride levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap‐to‐lesion height ratios, and significant upregulation of the vasculoprotective NADPH oxidase 4 expression. CONCLUSIONS: The tandem stenosis mouse model in combination with the application of streptozotocin represents a highly suitable and unique mouse model for studying plaque destabilization under diabetic conditions. Furthermore, for the first time, we provide evidence of plaque‐stabilizing effects of sodium‐glucose co‐transporter 2 inhibitor. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing antidiabetic drugs for the highly sought‐after potential to stabilize atherosclerotic plaques. John Wiley and Sons Inc. 2021-12-31 /pmc/articles/PMC9075188/ /pubmed/34970931 http://dx.doi.org/10.1161/JAHA.121.022761 Text en © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Brief Communication
Chen, Yung‐Chih
Jandeleit‐Dahm, Karin
Peter, Karlheinz
Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability
title Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability
title_full Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability
title_fullStr Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability
title_full_unstemmed Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability
title_short Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability
title_sort sodium‐glucose co‐transporter 2 (sglt2) inhibitor dapagliflozin stabilizes diabetes‐induced atherosclerotic plaque instability
topic Brief Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075188/
https://www.ncbi.nlm.nih.gov/pubmed/34970931
http://dx.doi.org/10.1161/JAHA.121.022761
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