广州医科大学Xi-yong Yu和Ying-hua Liu共同合作，近期取得重要工作进展。他们研究发现唑尼沙胺通过抑制蛋白酶体减轻压力过载引起的小鼠心肌肥厚。相关研究成果2023年12月14日在线发表于《中国药理学报》杂志上。

据介绍，心肌肥大是心肌的病理性增厚，最终导致心力衰竭。研究人员所在团队之前报道了唑尼沙胺，一种抗癫痫药物，可以减轻小鼠模型中由压力超负荷引起的心肌肥大和糖尿病心肌病。此外，研究人员发现蛋白酶体的抑制激活糖原合成激酶3（GSK-3）从而缓解心肌肥大，这是一种重要的抗肥大策略。

研究人员探讨了唑尼沙胺是否通过抑制蛋白酶体来预防压力超负荷引起的心肌肥大。通过经主动脉收缩（TAC）手术在小鼠体内诱导压力超负荷引起的心肌肥大。手术后两天，给小鼠服用唑尼沙胺（10，20，40 mg·kg⁻¹·d⁻¹）连续4周。研究人员发现，服用唑尼沙胺可显著减轻受损的心功能。

此外，唑尼沙胺给药显著抑制蛋白酶体活性以及20 S蛋白酶体（PSMB1、PSMB2和PSMB5）和19的蛋白酶体调节颗粒（RPT） S蛋白酶体（RPT1、RPT4）在TAC小鼠心脏组织中的表达。在原代新生大鼠心肌细胞（NRCM）中，唑尼沙胺（0.3 μM）预防血管紧张素II（Ang II）引发的心肌肥大，并显著抑制蛋白酶体活性、蛋白酶体亚基和蛋白酶体调节颗粒。在Ang II处理的NRCM中，研究人员发现18α-甘草次酸（18α-GA，2 mg/ml），一种蛋白酶体诱导剂，消除了唑尼沙胺对心肌肥大和蛋白酶体的保护作用。

此外，唑尼沙胺处理通过抑制GSK-3上游的磷酸化AKT（蛋白激酶B，PKB）和磷酸化肝激酶B1/AMP活化蛋白激酶（LKB1/AMPKα）来活化GSK-3。唑尼沙胺治疗还抑制了GSK-3的下游信号蛋白，包括细胞外信号调节激酶（ERK）和GATA结合蛋白4（GATA4），这两种蛋白都是肥大因子。

总之，这项研究强调了唑尼沙胺作为一种新的心肌肥大治疗剂的潜力，它通过抑制蛋白酶体显示出强大的抗肥大潜力。

附：英文原文

Title: Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition

Author: Wu, Qian, Liu, Wan-jie, Ma, Xin-yu, Chang, Ji-shuo, Zhao, Xiao-ya, Liu, Ying-hua, Yu, Xi-yong

Issue&Volume: 2023-12-14

Abstract: Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40mg·kg1·d1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3μM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3’s downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.

DOI: 10.1038/s41401-023-01191-7

Source: https://www.nature.com/articles/s41401-023-01191-7