Article

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation

Heng-hui Xu1,2,3, Sheng-xin Hao1,2,3, He-yang Sun1,2,3, Xin-xin Dong1,2,3, Yuan Lin1,2,3, Han Lou1,2,3, Li-min Zhao1,2,3, Ping-ping Tang1,2,3, Zi-jia Dou1,2,3, Jing-jing Han4, Meng-han Du1,2,3, Zhou-xiu Chen1,2,3, Philipp Kopylov5, Dmitry Shchekochikhin5, Xin Liu1,2,3, Yong Zhang1,2,3
1 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150000, China
2 State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150000, China
3 Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150000, China
4 Department of Pharmacy, Caoxian People’s Hospital, Heze 274400, China
5 Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, Russian Federation
Correspondence to: Xin Liu: freyaliuxin@163.com, Yong Zhang: hmuzhangyong@hotmail.com,
DOI: 10.1038/s41401-024-01307-7
Received: 27 November 2023
Accepted: 6 May 2024
Advance online: 11 June 2024

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.

Keywords: diabetic cardiomyopathy; tetrahydroberberrubine; RAGE; inflammation

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