Zonisamide alleviates cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting endoplasmic reticulum stress  

作　　者：Qian Wu Jia-hui Tian Yong-xiang He Yong-yin Huang Yu-qing Huang Gui-ping Zhang Jian-dong Luo Qin Xue Xi-yong Yu Ying-hua Liu 

机构地区：[1]The Fifth Affiliated Hospital,Key Laboratory of Molecular Target&Clinical Pharmacology and the State Key Laboratory of Respiratory Disease,School of Pharmaceutical Sciences,Guangzhou Medical University,Guangzhou 511436,China

出　　处：《Acta Pharmacologica Sinica》2021年第10期1587-1597,共11页中国药理学报（英文版）

基　　金：This work was supported by Natural Science Foundation of Guangdong Province(2014A030313485);Scientific and Technological Planning Program of Guangzhou(2017071010458);Municipal Education Bureau Program of Guangzhou(1201610286);Natural Science Foundation of Guangdong Province(2018A030313719)。

摘　　要：Antiepileptic drug zonisamide has been shown to be curative for Parkinson’s disease(PD)through increasing HMG-CoA reductase degradation protein 1(Hrd1)level and mitigating endoplasmic reticulum(ER)stress.Hrd1 is an ER-transmembrane E3 ubiquitin ligase,which is involved in cardiac dysfunction and cardiac hypertrophy in a mouse model of pressure overload.In this study,we investigated whether zonisamide alleviated cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting ER stress.The beneficial effects of zonisamide were assessed in two experimental models of cardiac hypertrophy:in rats subjected to abdominal aorta constriction(AAC)and treated with zonisamide(14,28,56 mg·kg^(−1)·d^(−1),i.g.)for 6 weeks as well as in neonatal rat cardiomyocytes(NRCMs)co-treated with Ang II(10μM)and zonisamide(0.3μM).Echocardiography analysis revealed that zonsiamide treatment significantly improved cardiac function in AAC rats.We found that zonsiamide treatment significantly attenuated cardiac hypertrophy and fibrosis,and suppressed apoptosis and ER stress in the hearts of AAC rats and in Ang II-treated NRCMs.Importantly,zonisamide markedly increased the expression of Hrd1 in the hearts of AAC rats and in Ang II-treated NRCMs.Furthermore,we demonstrated that zonisamide accelerated ER-associated protein degradation(ERAD)in Ang II-treated NRCMs;knockdown of Hrd1 abrogated the inhibitory effects of zonisamide on ER stress and cardiac hypertrophy.Taken together,our results demonstrate that zonisamide is effective in preserving heart structure and function in the experimental models of pathological cardiac hypertrophy.Zonisamide increases Hrd1 expression,thus preventing cardiac hypertrophy and improving the cardiac function of AAC rats.

关 键 词：ZONISAMIDE cardiac hypertrophy endoplasmic reticulum stress Hrd1 pressure overload neonatal rat cardiomyocytes(NRCMs) 

分 类 号：R542.2[医药卫生—心血管疾病] R96[医药卫生—内科学]