Abstract
Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg−1·d−1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 μM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Change history
23 January 2025
The original online version of this article was revised: "In this article fig. 1 as well as the legends of the supplementary figures have been updated."
30 January 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41401-025-01483-0
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Funding
This work was supported by the National Natural Science Foundation of China (82273919, 82270396), the HMU Marshal Initiative Funding (HMUMIF-21022) and the Science Foundation for the Excellent Youth Scholars of Heilongjiang Province (JJ2023YX0509).
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Design of the study: XL, YZ. Performance of the experiments: HHX, SXH, HYS, XXD, YL, HL, LMZ, PPT, ZJD, JJH, MHD, ZXC. Analysis of the data: HHX, SXH. Writing—original draft: HHX. Writing—review & editing: HHX, SXH, HYS, YL,HL, LMZ, PPT, ZJD, JJH, MHD. ZXC, PK, DS, XL, YZ.
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The use of animals was approved by the Ethics Committees of Harbin Medical University and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
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The original online version of this article was revised: “In this article fig. 1 as well as the legends of the supplementary figures have been updated.”
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Xu, Hh., Hao, Sx., Sun, Hy. et al. THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation. Acta Pharmacol Sin 45, 2107–2118 (2024). https://doi.org/10.1038/s41401-024-01307-7
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DOI: https://doi.org/10.1038/s41401-024-01307-7
