The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Acta Pharmacol Sin. 2021 Oct;42(10):1587-1597. doi: 10.1038/s41401-020-00585-1. Epub 2021 Jan 25.
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 · d, 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.
抗癫痫药佐米曲坦已被证明通过增加 HMG-CoA 还原酶降解蛋白 1（Hrd1）水平和减轻内质网（ER）应激对帕金森病（PD）具有治疗作用。Hrd1 是一种 ER 跨膜 E3 泛素连接酶，参与压力超负荷小鼠模型中心律失常和心肌肥厚。在这项研究中，我们研究了佐米曲坦是否通过增加 Hrd1 表达和抑制 ER 应激来减轻大鼠的心肌肥厚。在两种心肌肥厚实验模型中评估了佐米曲坦的有益作用：在接受腹主动脉缩窄（AAC）并接受佐米曲坦（14、28、56mg·kg·d，ig）治疗 6 周的大鼠以及在同时用 Ang II（10μM）和佐米曲坦（0.3μM）处理的新生大鼠心肌细胞（NRCMs）中。超声心动图分析表明，佐米曲坦治疗可显著改善 AAC 大鼠的心脏功能。我们发现，佐米曲坦治疗可显著减轻 AAC 大鼠心脏和 Ang II 处理的 NRCMs 中的心肌肥厚和纤维化，并抑制凋亡和 ER 应激。重要的是，佐米曲坦显著增加了 AAC 大鼠和 Ang II 处理的 NRCMs 中的 Hrd1 表达。此外，我们证明佐米曲坦可加速 Ang II 处理的 NRCMs 中的 ER 相关蛋白降解（ERAD）；Hrd1 的敲低消除了佐米曲坦对 ER 应激和心肌肥厚的抑制作用。总之，我们的研究结果表明，佐米曲坦在病理性心肌肥厚的实验模型中有效保护心脏结构和功能。佐米曲坦增加 Hrd1 表达，从而防止心肌肥厚并改善 AAC 大鼠的心脏功能。
