Zonisamide alleviates cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting endoplasmic reticulum stress
| Autor: | Jiandong Luo, Xi-Yong Yu, Yong-Xiang He, Yu-Qing Huang, Yong-Yin Huang, Qian Wu, Yinghua Liu, Jia-Hui Tian, Gui-Ping Zhang, Qin Xue |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Cardiac function curve medicine.medical_specialty Ubiquitin-Protein Ligases Zonisamide Apoptosis Cardiomegaly Protein degradation Article Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Fibrosis Internal medicine medicine Animals Myocytes Cardiac Pharmacology (medical) Aorta Abdominal Pharmacology Pressure overload business.industry Endoplasmic reticulum Endoplasmic Reticulum-Associated Degradation General Medicine Endoplasmic Reticulum Stress medicine.disease Up-Regulation 030104 developmental biology Endocrinology 030220 oncology & carcinogenesis cardiovascular system Unfolded protein response business medicine.drug |
| Zdroj: | Acta Pharmacol Sin |
| ISSN: | 1745-7254 1671-4083 |
| DOI: | 10.1038/s41401-020-00585-1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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