Zonisamide,an antiepileptic drug,alleviates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress

• 作者: Jia-hui Tian Qian Wu Yong-xiang He Qi-ying Shen Mubarak Rekep Gui-ping Zhang Jian-dong Luo Qin Xue Ying-hua Liu
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: Cardiovascular Pharmacology
• 页码范围: 393-403
• 页数: 11页
• 语种: 英文

摘要

Endoplasmic reticulum stress(ER stress)plays a key role in the development of cardiac hypertrophy and diabetic cardiomyopathy(DCM).Zonisamide(ZNS)was originally developed as an antiepileptic drug.Studies have shown that ZNS suppresses ER stress-induced neuronal cell damage in the experimental models of Parkinson's disease.Herein,we investigated whether ZNS improved DCM by attenuating ER stress-induced apoptosis.C57BL/6J mice were fed with high-fat diet(HFD)and intraperitoneally injected with low-dose streptozotocin(STZ)to induce type 2 diabetes mellitus(T2DM),and then treated with ZNS(40 mg·kg-1·d-1,i.g.)for 16 weeks.We showed that ZNS administration slightly ameliorated the blood glucose levels,but significantly alleviated diabetes-induced cardiac dysfunction and hypertrophy.Furthermore,ZNS administration significantly inhibited the Bax and caspase-3 activity,upregulated Bcl-2 activity,and decreased the proportion of TUNEL-positive cells in heart tissues.We analyzed the hallmarks of ER stress in heart tissues,and revealed that ZNS administration significantly decreased the protein levels of GRP78,XBP-1 s,ATF6,PERK,ATF4,and CHOP,and elevated Hrd1 protein.In high glucose(HG)-treated primary cardiomyocytes,application of ZNS(3 μM)significantly alleviated HG-induced cardiomyocyte hypertrophy and apoptosis.ZNS application also suppressed activated ER stress in HG-treated cardiomyocytes.Moreover,preapplication of the specific ER stress inducer tunicamycin(10ng/mL)eliminated the protective effects of ZNS against HG-induced cardiac hypertrophy and ER stress-mediated apoptosis.Our findings suggest that ZNS improves the cardiac diastolic function in diabetic mice and prevents T2DM-induced cardiac hypertrophy by attenuating ER stress-mediated apoptosis.