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Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice

Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mec...

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Autores principales: Deng, Ya-Wen, Liu, Fei, Li, Zhi-Tong, Gao, Jing-Han, Zhao, Yong, Yang, Xiao-Lei, Xia, Yun-Long
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9588458/
https://www.ncbi.nlm.nih.gov/pubmed/35941186
http://dx.doi.org/10.1038/s41374-022-00819-2
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author Deng, Ya-Wen
Liu, Fei
Li, Zhi-Tong
Gao, Jing-Han
Zhao, Yong
Yang, Xiao-Lei
Xia, Yun-Long
author_facet Deng, Ya-Wen
Liu, Fei
Li, Zhi-Tong
Gao, Jing-Han
Zhao, Yong
Yang, Xiao-Lei
Xia, Yun-Long
author_sort Deng, Ya-Wen
collection PubMed
description Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 μL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6–8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT–qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.
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spelling pubmed-95884582022-10-25 Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice Deng, Ya-Wen Liu, Fei Li, Zhi-Tong Gao, Jing-Han Zhao, Yong Yang, Xiao-Lei Xia, Yun-Long Lab Invest Article Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 μL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6–8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT–qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice. Nature Publishing Group US 2022-08-08 2022 /pmc/articles/PMC9588458/ /pubmed/35941186 http://dx.doi.org/10.1038/s41374-022-00819-2 Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Deng, Ya-Wen
Liu, Fei
Li, Zhi-Tong
Gao, Jing-Han
Zhao, Yong
Yang, Xiao-Lei
Xia, Yun-Long
Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice
title Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice
title_full Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice
title_fullStr Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice
title_full_unstemmed Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice
title_short Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice
title_sort hyperglycemia promotes myocardial dysfunction via the ers-mapk10 signaling pathway in db/db mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9588458/
https://www.ncbi.nlm.nih.gov/pubmed/35941186
http://dx.doi.org/10.1038/s41374-022-00819-2
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