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KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling
Aims: Krüppel-like Factor 9 (KLF9) is a transcription factor that regulates multiple disease processes. Studies have focused on the role of KLF9 in the redox system. In this study, we aimed to explore the effect of KLF9 on diabetic cardiomyopathy. Methods and Results: Cardiac-specific overexpression...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9656075/ https://www.ncbi.nlm.nih.gov/pubmed/36359788 http://dx.doi.org/10.3390/cells11213393 |
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author | Li, Fangfang Peng, Jingfeng Feng, Hui Yang, Yiming Gao, Jianbo Liu, Chunrui Xu, Jie Zhao, Yanru Pan, Siyu Wang, Yixiao Xu, Luhong Qian, Wenhao Zong, Jing |
author_facet | Li, Fangfang Peng, Jingfeng Feng, Hui Yang, Yiming Gao, Jianbo Liu, Chunrui Xu, Jie Zhao, Yanru Pan, Siyu Wang, Yixiao Xu, Luhong Qian, Wenhao Zong, Jing |
author_sort | Li, Fangfang |
collection | PubMed |
description | Aims: Krüppel-like Factor 9 (KLF9) is a transcription factor that regulates multiple disease processes. Studies have focused on the role of KLF9 in the redox system. In this study, we aimed to explore the effect of KLF9 on diabetic cardiomyopathy. Methods and Results: Cardiac-specific overexpression or silencing of KLF9 in C57BL/6 J mice was induced with an adeno-associated virus 9 (AAV9) delivery system. Mice were also subjected to streptozotocin injection to establish a diabetic cardiomyopathy model. In addition, neonatal rat cardiomyocytes were used to assess the possible role of KLF9 in vitro by incubation with KLF9 adenovirus or small interfering RNA against KLF9. To clarify the involvement of peroxisome proliferator-activated receptors (PPARγ), mice were subjected to GW9662 injection to inhibit PPARγ. KLF9 was upregulated in the hearts of mice with diabetic cardiomyopathy and in cardiomyocytes. In addition, KLF9 overexpression in the heart deteriorated cardiac function and aggravated hypertrophic fibrosis, the inflammatory response and oxidative stress in mice with diabetic cardiomyopathy. Conversely, cardiac-specific silencing of KLF9 ameliorated cardiac dysfunction and alleviated hypertrophy, fibrosis, the cardiac inflammatory response and oxidative stress. In vitro, KLF9 silencing in cardiomyocytes enhanced inflammatory cytokine release and oxidative stress; KLF9 overexpression increased these detrimental responses. Moreover, KLF9 was found to regulate the transcription of PPARγ, which suppressed the expression and nuclear translocation of nuclear Factor E2-related Factor 2 (NRF2). In mice injected with a PPARγ inhibitor, the protective effects of KLF9 knockdown on diabetic cardiomyopathy were counteracted by GW9662 injection. Conclusions: KLF9 aggravates cardiac dysfunction, the inflammatory response and oxidative stress in mice with diabetic cardiomyopathy. KLF9 may become a therapeutic target for diabetic cardiomyopathy. |
format | Online Article Text |
id | pubmed-9656075 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96560752022-11-15 KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling Li, Fangfang Peng, Jingfeng Feng, Hui Yang, Yiming Gao, Jianbo Liu, Chunrui Xu, Jie Zhao, Yanru Pan, Siyu Wang, Yixiao Xu, Luhong Qian, Wenhao Zong, Jing Cells Article Aims: Krüppel-like Factor 9 (KLF9) is a transcription factor that regulates multiple disease processes. Studies have focused on the role of KLF9 in the redox system. In this study, we aimed to explore the effect of KLF9 on diabetic cardiomyopathy. Methods and Results: Cardiac-specific overexpression or silencing of KLF9 in C57BL/6 J mice was induced with an adeno-associated virus 9 (AAV9) delivery system. Mice were also subjected to streptozotocin injection to establish a diabetic cardiomyopathy model. In addition, neonatal rat cardiomyocytes were used to assess the possible role of KLF9 in vitro by incubation with KLF9 adenovirus or small interfering RNA against KLF9. To clarify the involvement of peroxisome proliferator-activated receptors (PPARγ), mice were subjected to GW9662 injection to inhibit PPARγ. KLF9 was upregulated in the hearts of mice with diabetic cardiomyopathy and in cardiomyocytes. In addition, KLF9 overexpression in the heart deteriorated cardiac function and aggravated hypertrophic fibrosis, the inflammatory response and oxidative stress in mice with diabetic cardiomyopathy. Conversely, cardiac-specific silencing of KLF9 ameliorated cardiac dysfunction and alleviated hypertrophy, fibrosis, the cardiac inflammatory response and oxidative stress. In vitro, KLF9 silencing in cardiomyocytes enhanced inflammatory cytokine release and oxidative stress; KLF9 overexpression increased these detrimental responses. Moreover, KLF9 was found to regulate the transcription of PPARγ, which suppressed the expression and nuclear translocation of nuclear Factor E2-related Factor 2 (NRF2). In mice injected with a PPARγ inhibitor, the protective effects of KLF9 knockdown on diabetic cardiomyopathy were counteracted by GW9662 injection. Conclusions: KLF9 aggravates cardiac dysfunction, the inflammatory response and oxidative stress in mice with diabetic cardiomyopathy. KLF9 may become a therapeutic target for diabetic cardiomyopathy. MDPI 2022-10-27 /pmc/articles/PMC9656075/ /pubmed/36359788 http://dx.doi.org/10.3390/cells11213393 Text en © 2022 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 Li, Fangfang Peng, Jingfeng Feng, Hui Yang, Yiming Gao, Jianbo Liu, Chunrui Xu, Jie Zhao, Yanru Pan, Siyu Wang, Yixiao Xu, Luhong Qian, Wenhao Zong, Jing KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling |
title | KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling |
title_full | KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling |
title_fullStr | KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling |
title_full_unstemmed | KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling |
title_short | KLF9 Aggravates Streptozotocin-Induced Diabetic Cardiomyopathy by Inhibiting PPARγ/NRF2 Signalling |
title_sort | klf9 aggravates streptozotocin-induced diabetic cardiomyopathy by inhibiting pparγ/nrf2 signalling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9656075/ https://www.ncbi.nlm.nih.gov/pubmed/36359788 http://dx.doi.org/10.3390/cells11213393 |
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