Nakajima Toshiaki, Haruyama Akiko, Fukuda Taira, Minami Kentaro, Nakajima Takafumi, Hasegawa Takaaki, Tokoi Seiko, Obi Syotaro, Oguri Gaku, Sakuma Masashi, Shibasaki Ikuko, Fukuda Hirotsugu, Toyoda Shigeru
Department of Cardiovascular Medicine, School of Medicine, Dokkyo Medical University, Shimotsuga-gun, Tochigi, Japan.
Department of Liberal Arts and Sciences, Kanagawa University of Human Services, Yokosuka, Kanagawa, Japan.
Int J Cardiol Heart Vasc. 2025 Mar 17;57:101647. doi: 10.1016/j.ijcha.2025.101647. eCollection 2025 Apr.
Neprilysin (NEP) is a membrane-bound neutral endopeptidase with various physiological functions. We investigated the roles of NEP in atrial fibrotic remodeling and atrial fibrillation (AF) in patients undergoing cardiovascular surgery.
Atrial tissue samples were obtained from left atrium (LA) appendages, and mRNA expression level was analyzed by real-time reverse transcription polymerase chain reaction in 61 cases (25 paroxysmal fibrillation (PAF), 36 AF). Adipose tissue (AT) mRNA expression levels were also analyzed. Western blotting and immunohistochemical staining were used for determining tissue protein expression. Serum NEP levels were measured by enzyme-linked immunosorbent assay (ELISA). Two-dimensional speckle tracking echocardiography was performed to measure mean left atrial reservoir strain (mLASr) to evaluate atrial remodeling in pre-operative patients and control participants.
Immunohistochemical staining and western blotting revealed NEP expression in both AT and LA. Serum NEP levels did not correlate with NEP mRNA or protein expression in AT and LA. NEP mRNA expression levels correlated with fibrosis-related gene expression. NEP mRNA, protein, and fibrosis-related gene expression levels increased in PAF patients with low mLASr compared with high mLASr. PAF patients with high NEP mRNA expression showed increased fibrosis-related gene expression compared with those with low NEP expression. Multiple regression analysis revealed that NEP mRNA expression level was an independent variable for predicting fibrosis-related gene expression, whereas NOX4 and NLRP3 were independent variables for predicting NEP expression levels.
Increased atrial expression of NEP is linked to atrial fibrotic remodeling, and the development of AF in patients undergoing cardiovascular surgery.
中性肽链内切酶（NEP）是一种具有多种生理功能的膜结合中性内肽酶。我们研究了NEP在接受心血管手术患者的心房纤维化重塑和心房颤动（AF）中的作用。
从左心房（LA）心耳获取心房组织样本，采用实时逆转录聚合酶链反应分析61例患者（25例阵发性房颤（PAF），36例AF）的mRNA表达水平。同时分析脂肪组织（AT）的mRNA表达水平。采用蛋白质免疫印迹法和免疫组织化学染色法测定组织蛋白表达。采用酶联免疫吸附测定法（ELISA）检测血清NEP水平。术前对患者和对照参与者进行二维斑点追踪超声心动图检查，测量平均左心房储备应变（mLASr）以评估心房重塑。
免疫组织化学染色和蛋白质免疫印迹法显示AT和LA中均有NEP表达。血清NEP水平与AT和LA中的NEP mRNA或蛋白表达无关。NEP mRNA表达水平与纤维化相关基因表达相关。与高mLASr的PAF患者相比，低mLASr的PAF患者的NEP mRNA、蛋白及纤维化相关基因表达水平升高。与低NEP表达的PAF患者相比，高NEP mRNA表达的PAF患者的纤维化相关基因表达增加。多元回归分析显示，NEP mRNA表达水平是预测纤维化相关基因表达的独立变量，而NOX4和NLRP3是预测NEP表达水平的独立变量。
心房NEP表达增加与心房纤维化重塑以及接受心血管手术患者的AF发生有关。
