Zhao Jieqiong, Lei Yonghong, Yang Yanping, Gao Haibo, Gai Zhongchao, Li Xue
Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi'an, 710038 Shaanxi People's Republic of China.
Department of Plastic Surgery, General Hospital of Chinese PLA, Beijing, 100853 People's Republic of China.
Cell Biosci. 2020 May 24;10:72. doi: 10.1186/s13578-020-00434-y. eCollection 2020.
Arginine vasopressin (AVP) is elevated in patients with heart failure, and the increase in the AVP concentration in plasma is positively correlated with disease severity and mortality. Metoprolol (Met) is a beta blocker that is widely used in the clinic to treat pathological cardiac hypertrophy and to improve heart function. However, the specific mechanism by which Met alleviates AVP-induced pathological cardiac hypertrophy is still unknown. Our current study aimed to evaluate the inhibitory effects of Met on AVP-induced cardiomyocyte hypertrophy and the underlying mechanisms.
AVP alone or AVP plus Met was added to the wild type or AKT1-overexpressing rat cardiac H9C2 cell line. The cell surface areas and ANP/BNP/β-MHC expressions were used to evaluate the levels of hypertrophy. Western bolting was used to analyze AKT1/P-AKT1, AKT2/P-AKT2, total AKT, SERCA2, and Phospholamban (PLN) expression. Fluo3-AM was used to measure the intracellular Ca stores.
In the current study, we found that AKT1 but not AKT2 mediated the pathogenesis of AVP-induced cardiomyocyte hypertrophy. Sustained stimulation (48 h) with AVP led to hypertrophy in the H9C2 rat cardiomyocytes, resulting in the downregulation of AKT1 (0.48 fold compared to control) and SERCA2 (0.62 fold), the upregulation of PLN (1.32 fold), and the increase in the cytoplasmic calcium concentration (1.52 fold). In addition, AKT1 overexpression increased the expression of SERCA2 (1.34 fold) and decreased the expression of PLN (0.48 fold) in the H9C2 cells. Moreover, we found that Met could attenuate the AVP-induced changes in AKT1, SERCA2 and PLN expression and decreased the cytoplasmic calcium concentration in the H9C2 cells.
Our results demonstrated that the AKT1-SERCA2 cascade served as an important regulatory pathway in AVP-induced pathological cardiac hypertrophy.
心力衰竭患者体内精氨酸加压素（AVP）水平升高，血浆中AVP浓度的增加与疾病严重程度和死亡率呈正相关。美托洛尔（Met）是一种β受体阻滞剂，在临床上广泛用于治疗病理性心肌肥厚和改善心脏功能。然而，Met减轻AVP诱导的病理性心肌肥厚的具体机制仍不清楚。我们目前的研究旨在评估Met对AVP诱导的心肌细胞肥大的抑制作用及其潜在机制。
将单独的AVP或AVP加Met添加到野生型或AKT1过表达的大鼠心脏H9C2细胞系中。使用细胞表面积和ANP/BNP/β-MHC表达来评估肥大水平。采用蛋白质免疫印迹法分析AKT1/P-AKT1、AKT2/P-AKT2、总AKT、肌浆网钙ATP酶2（SERCA2）和受磷蛋白（PLN）的表达。使用Fluo3-AM测量细胞内钙储存。
在本研究中，我们发现AKT1而非AKT2介导了AVP诱导的心肌细胞肥大的发病机制。AVP持续刺激（48小时）导致H9C2大鼠心肌细胞肥大，导致AKT1（与对照组相比为0.48倍）和SERCA2（0.62倍）下调，PLN上调（1.32倍），以及细胞质钙浓度增加（1.52倍）。此外，AKT1过表达增加了H9C2细胞中SERCA2的表达（1.34倍）并降低了PLN的表达（0.48倍）。此外，我们发现Met可以减弱AVP诱导的AKT1、SERCA2和PLN表达的变化，并降低H9C2细胞中的细胞质钙浓度。
我们的结果表明，AKT1-SERCA2级联在AVP诱导的病理性心肌肥厚中起重要调节作用。
