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THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation

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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Fig. 1: THBru improves cardiac dysfunction in db/db mice.
Fig. 2: THBru directly binds to RAGE and modulates the expression of RAGE protein.
Fig. 3: THBru reduces inflammatory responses in db/db mice by inhibiting PI3K/AKT/NF-κB pathway.
Fig. 4: THBru ameliorates cardiomyocyte damage and inflammatory response induced by high glucose.
Fig. 5: THBru Inhibits RAGE-dependent signaling pathway in cardiomyocytes exposed to HG.
Fig. 6: Overexpression of RAGE reversed the protective effects of THBru in HG-treated cardiomyocyte.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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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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Contributions

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.

Corresponding authors

Correspondence to Xin Liu or Yong Zhang.

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The authors declare no competing interests.

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All of the authors have declared their consent for this publication.

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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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Xu, Hh., Hao, Sx., Sun, Hy. et al. THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01307-7

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