Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition  

作　　者：Qian Wu Wan-jie Liu Xin-yu Ma Ji-shuo Chang Xiao-ya Zhao Ying-hua Liu Xi-yong Yu 

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

出　　处：《Acta Pharmacologica Sinica》2024年第4期738-750,共13页中国药理学报（英文版）

基　　金：supported by the National Key Research and Development Program of China(2022YFE0209700);Basic and Applied Basic Research Foundation of Guangzhou city(G23151013);Traditional Chinese Medicine Research Project of Guangdong Province(20241180);First-class Specialty Construction Project of Guangzhou Medical University(02-408-2304-13048XM);Discipline Construction Project of Guangzhou Medical University(02-445-2301192XM,02-445-2301223XM,02-445-2301191XM);Quality Project of Guangdong Province(01-408-2301064XM);Education Reform Project of Guangzhou Medical University(01-408-2301033XM);First-class Specialty Construction Project of Guangzhou Medical University(02-408-2304-13014XM);Research capacity improvement project of Guangzhou Medical University(02-410-2302365XM);Basic and Applied Basic Research Project of Guangzhou city(2023A04J0565).

摘　　要：Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg^(−1)·d^(−1), i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 μM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3’s downstream signaling proteins, including extracellular signal-regulated k

关 键 词：myocardial hypertrophy pressure overload ZONISAMIDE PROTEASOME glycogen synthesis kinase 3(GSK-3) neonatal rat cardiomyocytes angiotensin II 

分 类 号：R542.2[医药卫生—心血管疾病]