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

Acta Pharmacologica Sinica volume 45, pages 738–750 (2024)Cite this article

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, 40 mg·kg−1·d−1, 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 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 μM) 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, 2 mg/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.

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Fig. 1: Zonisamide improved cardiac function in mice with pressure overload.
Fig. 2: Zonisamide alleviated myocardial hypertrophy and myocardial fibrosis in the hearts of mice with pressure overload induced by TAC.
Fig. 3: Zonisamide alleviated angiotensin II (Ang II)-triggered myocardial hypertrophy and myocardial fibrosis in vitro.
Fig. 4: Zonisamide inhibited the proteasome activities and subunits in TAC mice and hypertrophic NRCMs.
Fig. 5: Zonisamide alleviated myocardial hypertrophy by suppressing activated proteasome.
Fig. 6: The effects of zonisamide on glycogen synthesis kinase 3 (GSK-3), AKT (protein kinase B, PKB), liver kinase B1(LKB1), AMP-activated protein kinase (AMPKα), extracellular signal-regulated kinase (ERK), and GATA binding protein 4 (GATA4).
Fig. 7: Crystal structure and bindings of zonisamide with proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2, and PSMB5), and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4).
Fig. 8: Schematic diagram of zonisamide on pressure overload-induced myocardial hypertrophy.

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Acknowledgements

This study was supported by the National Key Research and Development Program of China (2022YFE0209700), Basic and Applied Basic Research Foundation of Guangzhou city (G23151013), Traditional Chinese Medicine Research Project of Guangdong Province (20241180), First-class Specialty Construction Project of Guangzhou Medical University (02-408-2304-13048XM), Discipline Construction Project of Guangzhou Medical University (02-445-2301192XM, 02-445-2301223XM, 02-445-2301191XM), Quality Project of Guangdong Province (01-408-2301064XM), Education Reform Project of Guangzhou Medical University (01-408-2301033XM), First-class Specialty Construction Project of Guangzhou Medical University (02-408-2304-13014XM), Research capacity improvement project of Guangzhou Medical University (02-410-2302365XM), and Basic and Applied Basic Research Project of Guangzhou city (2023A04J0565).

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  1. Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

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

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Contributions

QW designed the study; QW carried out the study and wrote the paper; QW performed the experiments; WJL, XYM, JSC, and XYZ participated in the animal experiment; XYY and YHL conceived, and supervised the study and helped in discussing the data.

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Correspondence to Ying-hua Liu or Xi-yong Yu.

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Wu, Q., Liu, Wj., Ma, Xy. et al. Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition. Acta Pharmacol Sin 45, 738–750 (2024). https://doi.org/10.1038/s41401-023-01191-7

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