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Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade

Cardiovascular disease is a common diabetic complication that can arise when cardiac fibroblasts transition into myofibroblasts. Myofibroblast transition can be induced by advanced glycated end products (AGEs) present in the extracellular matrix (ECM) activating RAGE (receptor for advanced glycated...

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Autores principales: Burr, Stephanie D., Stewart, James A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224555/
https://www.ncbi.nlm.nih.gov/pubmed/34067282
http://dx.doi.org/10.3390/cells10061286
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author Burr, Stephanie D.
Stewart, James A.
author_facet Burr, Stephanie D.
Stewart, James A.
author_sort Burr, Stephanie D.
collection PubMed
description Cardiovascular disease is a common diabetic complication that can arise when cardiac fibroblasts transition into myofibroblasts. Myofibroblast transition can be induced by advanced glycated end products (AGEs) present in the extracellular matrix (ECM) activating RAGE (receptor for advanced glycated end products) to elicit intracellular signaling. The levels of AGEs are higher under diabetic conditions due to the hyperglycemic conditions present in diabetics. AGE/RAGE signaling has been shown to alter protein expression and ROS production in cardiac fibroblasts, resulting in changes in cellular function, such as migration and contraction. Recently, a small GTPase, Rap1a, has been identified to overlap the AGE/RAGE signaling cascade and mediate changes in protein expression. While Rap1a has been shown to impact AGE/RAGE-induced protein expression, there are currently no data examining the impact Rap1a has on AGE/RAGE-induced cardiac fibroblast function. Therefore, we aimed to determine the impact of Rap1a on AGE/RAGE-mediated cardiac fibroblast contraction, as well as the influence isolated diabetic ECM has on facilitating these effects. In order to address this idea, genetically different cardiac fibroblasts were embedded in 3D collagen matrices consisting of collagen isolated from either non-diabetic of diabetic mice. Fibroblasts were treated with EPAC and/or exogenous AGEs, which was followed by assessment of matrix contraction, protein expression (α-SMA, SOD-1, and SOD-2), and hydrogen peroxide production. The results showed Rap1a overlaps the AGE/RAGE cascade to increase the myofibroblast population and generation of ROS production. The increase in myofibroblasts and oxidative stress appeared to contribute to increased matrix contraction, which was further exacerbated by diabetic conditions. Based off these results, we determined that Rap1a was essential in mediating the response of cardiac fibroblasts to AGEs within diabetic collagen.
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spelling pubmed-82245552021-06-25 Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade Burr, Stephanie D. Stewart, James A. Cells Article Cardiovascular disease is a common diabetic complication that can arise when cardiac fibroblasts transition into myofibroblasts. Myofibroblast transition can be induced by advanced glycated end products (AGEs) present in the extracellular matrix (ECM) activating RAGE (receptor for advanced glycated end products) to elicit intracellular signaling. The levels of AGEs are higher under diabetic conditions due to the hyperglycemic conditions present in diabetics. AGE/RAGE signaling has been shown to alter protein expression and ROS production in cardiac fibroblasts, resulting in changes in cellular function, such as migration and contraction. Recently, a small GTPase, Rap1a, has been identified to overlap the AGE/RAGE signaling cascade and mediate changes in protein expression. While Rap1a has been shown to impact AGE/RAGE-induced protein expression, there are currently no data examining the impact Rap1a has on AGE/RAGE-induced cardiac fibroblast function. Therefore, we aimed to determine the impact of Rap1a on AGE/RAGE-mediated cardiac fibroblast contraction, as well as the influence isolated diabetic ECM has on facilitating these effects. In order to address this idea, genetically different cardiac fibroblasts were embedded in 3D collagen matrices consisting of collagen isolated from either non-diabetic of diabetic mice. Fibroblasts were treated with EPAC and/or exogenous AGEs, which was followed by assessment of matrix contraction, protein expression (α-SMA, SOD-1, and SOD-2), and hydrogen peroxide production. The results showed Rap1a overlaps the AGE/RAGE cascade to increase the myofibroblast population and generation of ROS production. The increase in myofibroblasts and oxidative stress appeared to contribute to increased matrix contraction, which was further exacerbated by diabetic conditions. Based off these results, we determined that Rap1a was essential in mediating the response of cardiac fibroblasts to AGEs within diabetic collagen. MDPI 2021-05-22 /pmc/articles/PMC8224555/ /pubmed/34067282 http://dx.doi.org/10.3390/cells10061286 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Burr, Stephanie D.
Stewart, James A.
Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade
title Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade
title_full Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade
title_fullStr Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade
title_full_unstemmed Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade
title_short Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade
title_sort rap1a regulates cardiac fibroblast contraction of 3d diabetic collagen matrices by increased activation of the age/rage cascade
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224555/
https://www.ncbi.nlm.nih.gov/pubmed/34067282
http://dx.doi.org/10.3390/cells10061286
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