THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation  

作　　者：Heng-hui Xu Sheng-xin Hao He-yang Sun Xin-xin Dong Yuan Lin Han Lou Li-min Zhao Ping-ping Tang Zi-jia Dou Jing-jing Han Meng-han Du Zhou-xiu Chen Philipp Kopylov Dmitry Shchekochikhin Xin Liu Yong Zhang 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2024年第10期2107-2118,共12页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82273919,82270396);the HMU Marshal Initiative Funding(HMUMIF-21022);the Science Foundation for the Excellent Youth Scholars of Heilongjiang Province(JJ2023YX0509).

摘　　要：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(20,40μM)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.

关 键 词：diabetic cardiomyopathy tetrahydroberberrubine RAGE INFLAMMATION 

分 类 号：R587.2[医药卫生—内分泌] R542.2[医药卫生—内科学]