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Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway

PURPOSE: Diabetes mellitus is an independent risk factor for atrial fibrillation (AF), which may be related to accumulation of advanced glycation end products (AGEs). However, the mechanisms involved are not completely clear. Abnormality of gap junction proteins, especially connexin 43 (Cx43) and co...

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Autores principales: Yang, Fan, Liu, Huan-Huan, Zhang, Lei, Zhang, Xiao-Lu, Zhang, Jie, Li, Feng, Zhao, Ning, Zhang, Zhi-Yuan, Kong, Qi, Liu, Xiao-Yu, Wu, Ying, Yu, Zhi-Ming, Qian, Ling-Ling, Wang, Ru-Xing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557968/
https://www.ncbi.nlm.nih.gov/pubmed/37810573
http://dx.doi.org/10.2147/DMSO.S419189
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author Yang, Fan
Liu, Huan-Huan
Zhang, Lei
Zhang, Xiao-Lu
Zhang, Jie
Li, Feng
Zhao, Ning
Zhang, Zhi-Yuan
Kong, Qi
Liu, Xiao-Yu
Wu, Ying
Yu, Zhi-Ming
Qian, Ling-Ling
Wang, Ru-Xing
author_facet Yang, Fan
Liu, Huan-Huan
Zhang, Lei
Zhang, Xiao-Lu
Zhang, Jie
Li, Feng
Zhao, Ning
Zhang, Zhi-Yuan
Kong, Qi
Liu, Xiao-Yu
Wu, Ying
Yu, Zhi-Ming
Qian, Ling-Ling
Wang, Ru-Xing
author_sort Yang, Fan
collection PubMed
description PURPOSE: Diabetes mellitus is an independent risk factor for atrial fibrillation (AF), which may be related to accumulation of advanced glycation end products (AGEs). However, the mechanisms involved are not completely clear. Abnormality of gap junction proteins, especially connexin 43 (Cx43) and connexin 40 (Cx40) in atrial myocytes, is an important cause of increased susceptibility of AF. The aim of our work is to investigate the mechanism of dysregulated Cx43 and Cx40 in atrial myocytes of diabetic rats. METHODS: We established a type 1 diabetic rat model by intraperitoneal injection of streptozotocin. HL-1 cells and primary rat atrial myocytes were treated with AGEs in vitro. Using Western blotting, immunofluorescence staining, immunohistochemistry, and lucifer yellow diffusion measurements, we investigated dysregulation of Cx43 and Cx40 and its mechanism in atrial myocytes of diabetic rats. RESULTS: Accumulation of AGEs was found in diabetic rats. The expression of Cx43 and Cx40 was reduced in the atrium of diabetic rats, accompanied by the decrease of phosphorylated Adenosine 5’-monophosphate-activated protein kinase (p-AMPK). Similar results were found in cultured HL-1 cells and primary rat atrial myocytes, suggesting a role of AGEs on gap junction proteins. An AMPK agonist, 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), reversed the down-regulated Cx43 expression induced by AGEs stimulation. More importantly, lucifer yellow diffusion assay showed that AGEs significantly affected gap junctional function, and these changes were reversed by AICAR. CONCLUSION: Thus, we conclude that AGEs cause dysregulation of Cx43 and Cx40 in diabetic atria via the AMPK pathway, thereby leading to gap junction dysfunction, which may contribute to the increased AF susceptibility in diabetes.
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spelling pubmed-105579682023-10-07 Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway Yang, Fan Liu, Huan-Huan Zhang, Lei Zhang, Xiao-Lu Zhang, Jie Li, Feng Zhao, Ning Zhang, Zhi-Yuan Kong, Qi Liu, Xiao-Yu Wu, Ying Yu, Zhi-Ming Qian, Ling-Ling Wang, Ru-Xing Diabetes Metab Syndr Obes Original Research PURPOSE: Diabetes mellitus is an independent risk factor for atrial fibrillation (AF), which may be related to accumulation of advanced glycation end products (AGEs). However, the mechanisms involved are not completely clear. Abnormality of gap junction proteins, especially connexin 43 (Cx43) and connexin 40 (Cx40) in atrial myocytes, is an important cause of increased susceptibility of AF. The aim of our work is to investigate the mechanism of dysregulated Cx43 and Cx40 in atrial myocytes of diabetic rats. METHODS: We established a type 1 diabetic rat model by intraperitoneal injection of streptozotocin. HL-1 cells and primary rat atrial myocytes were treated with AGEs in vitro. Using Western blotting, immunofluorescence staining, immunohistochemistry, and lucifer yellow diffusion measurements, we investigated dysregulation of Cx43 and Cx40 and its mechanism in atrial myocytes of diabetic rats. RESULTS: Accumulation of AGEs was found in diabetic rats. The expression of Cx43 and Cx40 was reduced in the atrium of diabetic rats, accompanied by the decrease of phosphorylated Adenosine 5’-monophosphate-activated protein kinase (p-AMPK). Similar results were found in cultured HL-1 cells and primary rat atrial myocytes, suggesting a role of AGEs on gap junction proteins. An AMPK agonist, 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), reversed the down-regulated Cx43 expression induced by AGEs stimulation. More importantly, lucifer yellow diffusion assay showed that AGEs significantly affected gap junctional function, and these changes were reversed by AICAR. CONCLUSION: Thus, we conclude that AGEs cause dysregulation of Cx43 and Cx40 in diabetic atria via the AMPK pathway, thereby leading to gap junction dysfunction, which may contribute to the increased AF susceptibility in diabetes. Dove 2023-10-02 /pmc/articles/PMC10557968/ /pubmed/37810573 http://dx.doi.org/10.2147/DMSO.S419189 Text en © 2023 Yang et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Yang, Fan
Liu, Huan-Huan
Zhang, Lei
Zhang, Xiao-Lu
Zhang, Jie
Li, Feng
Zhao, Ning
Zhang, Zhi-Yuan
Kong, Qi
Liu, Xiao-Yu
Wu, Ying
Yu, Zhi-Ming
Qian, Ling-Ling
Wang, Ru-Xing
Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway
title Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway
title_full Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway
title_fullStr Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway
title_full_unstemmed Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway
title_short Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway
title_sort advanced glycation end products downregulate connexin 43 and connexin 40 in diabetic atrial myocytes via the ampk pathway
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557968/
https://www.ncbi.nlm.nih.gov/pubmed/37810573
http://dx.doi.org/10.2147/DMSO.S419189
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