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Indole-3-propionic acid, a product of intestinal flora, inhibits the HDAC6/NOX2 signaling and relieves doxorubicin-induced cardiomyocyte damage
Affiliations- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Department of Traditional Chinese Medicine, Tongzhou Maternal and Child Health Hospital of Beijing, Beijing, China
open access
Abstract
The heart failure-gut hypothesis indicates that damage to intestinal mucosa leads to increased microbial translocation, resulting in alterations in metabolites entering the blood circulation. This process promotes the development of heart failure. This study aimed to reveal the involvement of indole-3-propionic acid (IPA), a microbiota-derived tryptophan metabolite, in heart failure. Human cardiomyocytes AC16 was treated with doxorubicin to induce in vitro heart failure model, the influences of IPA on the cellular viability, apoptosis, inflammation and oxidative stress were evaluated. Molecular docking and western blotting were used to initially illustrate the potential relationship between IPA and HDAC6. Through HDAC6 overexpression, its mediating role in the regulatory mechanism of IPA in the above aspects was further investigated. IPA was found to reduce the apoptosis, inflammation and oxidative stress in doxorubicin-treated cells. The visualized structure displayed that IPA bound to HDAC6 and that IPA reduced HDAC6 level. Additionally, HDAC6 overexpression reversed the regulation of IPA in the above aspects, indicating the HDAC6/NOX2 signals mediated the mechanism of IPA. Together, the present study revealed that IPA reduced oxidative stress, inflammatory response and apoptosis in cardiomyocytes via inhibiting the HDAC6/NOX2 signaling. The findings suggest that gut microbiota metabolites have potential in the treatment of heart failure.
Abstract
The heart failure-gut hypothesis indicates that damage to intestinal mucosa leads to increased microbial translocation, resulting in alterations in metabolites entering the blood circulation. This process promotes the development of heart failure. This study aimed to reveal the involvement of indole-3-propionic acid (IPA), a microbiota-derived tryptophan metabolite, in heart failure. Human cardiomyocytes AC16 was treated with doxorubicin to induce in vitro heart failure model, the influences of IPA on the cellular viability, apoptosis, inflammation and oxidative stress were evaluated. Molecular docking and western blotting were used to initially illustrate the potential relationship between IPA and HDAC6. Through HDAC6 overexpression, its mediating role in the regulatory mechanism of IPA in the above aspects was further investigated. IPA was found to reduce the apoptosis, inflammation and oxidative stress in doxorubicin-treated cells. The visualized structure displayed that IPA bound to HDAC6 and that IPA reduced HDAC6 level. Additionally, HDAC6 overexpression reversed the regulation of IPA in the above aspects, indicating the HDAC6/NOX2 signals mediated the mechanism of IPA. Together, the present study revealed that IPA reduced oxidative stress, inflammatory response and apoptosis in cardiomyocytes via inhibiting the HDAC6/NOX2 signaling. The findings suggest that gut microbiota metabolites have potential in the treatment of heart failure.
Keywords
gut microbiome metabolites, heart failure, doxorubicin, IPA, oxidative stress
About this articleTitle
Indole-3-propionic acid, a product of intestinal flora, inhibits the HDAC6/NOX2 signaling and relieves doxorubicin-induced cardiomyocyte damage
Journal
Issue
Article type
Original article
Published online
2023-07-05
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559
Article views/downloads
578
DOI
Pubmed
Keywords
gut microbiome metabolites
heart failure
doxorubicin
IPA
oxidative stress
Authors
Chunyan Li
Jingling Chang
Yueqi Wang
Guozhong Pan
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