Lu Yi, Zhao Ming, Liu Jin-Jun, He Xi, Yu Xiao-Jiang, Liu Long-Zhu, Sun Lei, Chen Li-Na, Zang Wei-Jin
Department of Pharmacology School of Basic Medical Sciences Xian Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
J Cell Mol Med. 2017 Sep;21(9):2106-2116. doi: 10.1111/jcmm.13133. Epub 2017 Mar 10.
Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload-induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β-myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4 pathway and suppression of the interaction of Orai1/STIM1.
心肌肥厚与自主神经失衡有关，其特征是交感神经活动增强和副交感神经控制减弱。副交感神经功能增强可改善心室功能。然而，吡啶斯的明（一种可逆性乙酰胆碱酯酶抑制剂）是否能抵消压力超负荷诱导的心肌肥厚尚不清楚。因此，本研究旨在确定吡啶斯的明是否能改善压力超负荷诱导的心肌肥厚，并确定其潜在机制。将大鼠进行假手术或腹主动脉缩窄手术，并给予或不给予吡啶斯的明治疗8周。使用PowerLab测定迷走神经活动和心脏功能。使用各种组织学染色评估心肌肥厚。通过蛋白质印迹和免疫沉淀对心肌肥厚的蛋白质标志物进行定量。压力超负荷导致迷走神经放电显著减少，心脏肥厚指数和心脏功能严重增加。吡啶斯的明通过抑制压力超负荷大鼠的乙酰胆碱酯酶来增加乙酰胆碱水平。基于左心室重量/体重的降低、心房利钠肽、脑利钠肽和β-肌球蛋白重链水平的抑制以及心脏纤维化的减少，吡啶斯的明显著减轻了心肌肥厚。这些作用伴随着心脏功能的显著改善。此外，吡啶斯的明抑制CaN/NFAT3/GATA4途径并抑制Orai1/STIM1复合物的形成。总之，压力超负荷导致心肌肥厚、心脏功能障碍和迷走神经放电显著减少。吡啶斯的明减轻了心肌肥厚并改善了心脏功能，这与胆碱能传递效率的提高（乙酰胆碱酯酶降低和乙酰胆碱增加）、CaN/NFAT3/GATA4途径的抑制以及Orai1/STIM1相互作用的抑制有关。
