@article{APS10283,
author = {Jia-hui Tian and Qian Wu and Yong-xiang He and Qi-ying Shen and Mubarak Rekep and Gui-ping Zhang and Jian-dong Luo and Qin Xue and Ying-hua Liu},
title = {Zonisamide, an antiepileptic drug, alleviates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress},
journal = {Acta Pharmacologica Sinica},
volume = {42},
number = {3},
year = {2021},
keywords = {},
abstract = {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-1s, 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 (10 ng/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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/10283}
}