Guo Zhen, Fan Di, Liu Fang-Yuan, Ma Shu-Qing, An Peng, Yang Dan, Wang Min-Yu, Yang Zheng, Tang Qi-Zhu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China.
Front Cardiovasc Med. 2022 Apr 25;9:821317. doi: 10.3389/fcvm.2022.821317. eCollection 2022.
Neuraminidase 1 (NEU1) participates in the response to multiple receptor signals and regulates various cellular metabolic behaviors. Importantly, it is closely related to the occurrence and progression of cardiovascular diseases. Because ischemic heart disease is often accompanied by impaired mitochondrial energy metabolism and oxidative stress. The purpose of this study was to investigate the functions and possible mechanisms of NEU1 in myocardial remodeling and mitochondrial metabolism induced by myocardial infarction (MI).
In this study, the MI-induced mouse mode, hypoxia-treated H9C2 cells model, and hypoxia-treated neonatal rat cardiomyocytes (NRCMs) model were constructed. Echocardiography and histological analysis were adopted to evaluate the morphology and function of the heart at the whole heart level. Western blot was adopted to determine the related expression level of signaling pathway proteins and mitochondria. Mitochondrial energy metabolism and oxidative stress were detected by various testing kits.
Neuraminidase 1 was markedly upregulated in MI cardiac tissue. Cardiomyocyte-specific NEU1 deficiency restored cardiac function, cardiac hypertrophy, and myocardial interstitial fibrosis. What is more, cardiomyocyte-specific NEU1 deficiency inhibited mitochondrial dysfunction and oxidative stress induced by MI. Further experiments found that the sirtuin-1/peroxisome proliferator-activated receptor γ coactivator α (SIRT1/PGC-1α) protein level in MI myocardium was down-regulated, which was closely related to the above-mentioned mitochondrial changes. Cardiomyocyte-specific NEU1 deficiency increased the expression of SIRT1, PGC-1α, and mitochondrial transcription factor A (TFAM); which improved mitochondrial metabolism and oxidative stress. Inhibition of SIRT1 activity or PGC-1α activity eliminated the beneficial effects of cardiomyocyte-specific NEU1 deficiency. PGC-1α knockout mice experiments verified that NEU1 inhibition restored cardiac function induced by MI through SIRT1/PGC-1α signaling pathway.
Cardiomyocyte-specific NEU1 deficiency can alleviate MI-induced myocardial remodeling, oxidative stress, and mitochondrial energy metabolism disorder. In terms of mechanism, the specific deletion of NEU1 may play a role by enhancing the SIRT1/PGC-1α signaling pathway. Therefore, cardiomyocyte-specific NEU1 may provide an alternative treatment strategy for heart failure post-MI.
神经氨酸酶1（NEU1）参与多种受体信号应答并调节多种细胞代谢行为。重要的是，它与心血管疾病的发生和发展密切相关。由于缺血性心脏病常伴有线粒体能量代谢受损和氧化应激。本研究旨在探讨NEU1在心肌梗死（MI）诱导的心肌重塑和线粒体代谢中的功能及可能机制。
本研究构建了MI诱导的小鼠模型、缺氧处理的H9C2细胞模型和缺氧处理的新生大鼠心肌细胞（NRCMs）模型。采用超声心动图和组织学分析在全心水平评估心脏的形态和功能。采用蛋白质免疫印迹法测定信号通路蛋白和线粒体的相关表达水平。通过各种检测试剂盒检测线粒体能量代谢和氧化应激。
神经氨酸酶1在MI心脏组织中显著上调。心肌细胞特异性NEU1缺陷可恢复心脏功能、心脏肥大和心肌间质纤维化。此外，心肌细胞特异性NEU1缺陷可抑制MI诱导的线粒体功能障碍和氧化应激。进一步实验发现，MI心肌中沉默调节蛋白1/过氧化物酶体增殖物激活受体γ共激活因子α（SIRT1/PGC-1α）蛋白水平下调，这与上述线粒体变化密切相关。心肌细胞特异性NEU1缺陷增加了SIRT1、PGC-1α和线粒体转录因子A（TFAM）的表达；改善了线粒体代谢和氧化应激。抑制SIRT1活性或PGC-1α活性消除了心肌细胞特异性NEU1缺陷的有益作用。PGC-1α基因敲除小鼠实验证实，NEU1抑制通过SIRT1/PGC-1α信号通路恢复MI诱导的心脏功能。
心肌细胞特异性NEU1缺陷可减轻MI诱导的心肌重塑、氧化应激和线粒体能量代谢紊乱。机制方面，NEU1的特异性缺失可能通过增强SIRT1/PGC-1α信号通路发挥作用。因此，心肌细胞特异性NEU1可能为MI后心力衰竭提供一种替代治疗策略。
