Abstract
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 (10 μM) and zonisamide (0.3 μM). 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.
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Acknowledgements
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). We are thankful to Dr. Xiao-yan Dai for her help in the figures’ rearrangement and language editing.
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QW and JHT designed the research; QW carried out the study and wrote the paper; QW, JHT, YXH, YYH, YQH, and GPZ performed the experiments; QX and JDL helped in discussing the data and writing the paper; YHL, XYY, QX conceived, designed, and supervised the study and wrote the paper.
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Wu, Q., Tian, Jh., He, Yx. et al. Zonisamide alleviates cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting endoplasmic reticulum stress. Acta Pharmacol Sin 42, 1587–1597 (2021). https://doi.org/10.1038/s41401-020-00585-1
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DOI: https://doi.org/10.1038/s41401-020-00585-1
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