Neuraminidase 1 is a driver of experimental cardiac hypertrophy
Neuraminidase 1 is a driver of experimental cardiac hypertrophy
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神经氨酸酶 1 是实验性心脏肥大的驱动因素
DOI：
10.1093/eurheartj/ehab347
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发表时间：
2021-06-28
影响因子：
39.3
通讯作者：
Qi, Lian-Wen
中科院分区：
文献类型：
--
作者：
Chen, Qian-Qian;Ma, Gaoxiang;Qi, Lian-Wen
尽管在治疗方面取得了相当大的进步，但关于心脏肥大最终导致心力衰竭的分子决定因素的证据仍然缺乏。神经氨酸酶是一类催化从糖蛋白或糖脂中裂解末端唾液酸的酶。本研究旨在描述神经氨酸酶在病理性心肌肥大中的作用，并确定针对哺乳动物神经氨酸酶的药物抑制剂。方法与结果神经氨酸酶1 （NEU1）在肥厚性心肌病小鼠和大鼠的心脏中高表达，肥厚性心肌病患者（n=7）与健康对照组（n=7）相比证实了这种表达升高。增加的NEU1主要通过与心肌肌钙蛋白t共定位于心肌细胞中，心肌细胞特异性NEU1缺乏减轻了主动脉横缩或盐酸异丙肾上腺素输注时的肥厚表型，而NEU1过表达则加剧了心肌肥厚的发生。机制上，免疫共沉淀结合质谱、染色质免疫共沉淀和荧光素酶检测表明NEU1易位到细胞核并与GATA4相互作用，导致胎儿基因（Nppa和Nppb）表达。虚拟筛选和实验验证从数百万种化合物中鉴定出一种新的化合物C-09，该化合物与人类NEU1具有良好的结合亲和力（KD = 0.38 μ M），并在细胞和动物模型中有效地阻止了心脏重构的发展。有趣的是，抗流感药物扎那米韦和奥司他韦有效抑制哺乳动物NEU1，并显示出新的心脏保护适应症。这项工作确定NEU1是心脏肥厚的关键驱动因素，抑制NEU1为心血管疾病的治疗开辟了一个全新的领域。
Aims Despite considerable therapeutic advances, there is still a dearth of evidence on the molecular determinants of cardiac hypertrophy that culminate in heart failure. Neuraminidases are a family of enzymes that catalyze the cleavage of terminal sialic acids from glycoproteins or glycolipids. This study sought to characterize the role of neuraminidases in pathological cardiac hypertrophy and identify pharmacological inhibitors targeting mammalian neuraminidases.Methods and results Neuraminidase 1 (NEU1) was highly expressed in hypertrophic hearts of mice and rats, and this elevation was confirmed in patients with hypertrophic cardiomyopathy (n=7) compared with healthy controls (n=7). The increased NEU1 was mainly localized in cardiomyocytes by co-localization with cardiac troponin T. Cardiomyocyte-specific NEU1 deficiency alleviated hypertrophic phenotypes in response to transverse aortic constriction or isoproterenol hydrochloride infusion, while NEU1 overexpression exacerbated the development of cardiac hypertrophy. Mechanistically, co-immunoprecipitation coupled with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated that NEU1 translocated into the nucleus and interacted with GATA4, leading to Foetal gene (Nppa and Nppb) expression. Virtual screening and experimental validation identified a novel compound C-09 from millions of compounds that showed favourable binding affinity to human NEU1 (KD = 0.38 mu M) and effectively prevented the development of cardiac remodelling in cellular and animal models. Interestingly, anti-influenza drugs zanamivir and oseltamivir effectively inhibited mammalian NEU1 and showed new indications of cardio-protection.Conclusions This work identifies NEU1 as a critical driver of cardiac hypertrophy and inhibition of NEU1 opens up an entirely new field of treatment for cardiovascular diseases.