Cardiovascular Institute, An Nan Hospital, China Medical University, Tainan, Taiwan.
Department of Medicine, China Medical University, Taichung, Taiwan.
PLoS One. 2018 Aug 28;13(8):e0202979. doi: 10.1371/journal.pone.0202979. eCollection 2018.
The long-term use of proton pump inhibitors (PPIs) has been shown to increase the risk of cardiovascular mortality, however the molecular mechanisms are unknown. Superoxide has been implicated in the regulation of nerve growth factor (NGF), a mediator of sympathetic innervation. The purpose of this study was to determine whether PPIs increase ventricular arrhythmias through magnesium-mediated superoxide production in infarcted rats. Male Wistar rats were randomly assigned to receive vehicle, omeprazole, omeprazole + magnesium sulfate, or famotidine treatment for 4 weeks starting 24 hours after the induction of myocardial infarction by ligating the coronary artery. Increased myocardial superoxide and nitrotyrosine levels were noted post-infarction, in addition to a significant upregulation of NGF expression on mRNA and protein levels. Sympathetic hyperinnervation after infarction was confirmed by measuring myocardial norepinephrine and immunofluorescent analysis. Compared with the vehicle, omeprazole-treated infarcted rats had significantly reduced myocardial magnesium content, increased oxidant production, and increased sympathetic innervation, which in turn increased ventricular arrhythmias. These effects were prevented by the coadministration of magnesium sulfate. In an in vivo study, an omeprazole-induced increase in NGF was associated with a superoxide pathway, which was further confirmed by an ex vivo study showing the attenuation of NGF levels after coadministration of the superoxide scavenger Tiron. Magnesium sulfate did not further attenuate NGF levels compared with omeprazole + Tiron. Our results indicate that the long-term administration of PPIs was associated with reduced tissue magnesium content and increased myocardial superoxide production, which exacerbated ventricular arrhythmias after infarction. Magnesium may be a potential target for PPI-related arrhythmias after infarction.
质子泵抑制剂（PPIs）的长期使用已被证明会增加心血管死亡率，但其分子机制尚不清楚。超氧化物已被牵涉到神经生长因子（NGF）的调节中，NGF 是交感神经支配的介质。本研究的目的是确定 PPI 是否通过镁介导的超氧化物产生增加梗死大鼠的室性心律失常。雄性 Wistar 大鼠随机分为接受载体、奥美拉唑、奥美拉唑+硫酸镁或法莫替丁治疗组，从冠状动脉结扎后 24 小时开始，连续 4 周。除了 NGF 表达的 mRNA 和蛋白水平显著上调外，还观察到心肌梗死后超氧化物和硝基酪氨酸水平增加。通过测量心肌去甲肾上腺素和免疫荧光分析证实了梗死后的交感神经过度支配。与载体相比，奥美拉唑治疗的梗死大鼠心肌镁含量明显降低，氧化应激产物增加，交感神经支配增加，从而导致室性心律失常增加。硫酸镁的共同给药可预防这些影响。在一项体内研究中，奥美拉唑诱导的 NGF 增加与超氧化物途径有关，这进一步通过一项离体研究得到证实，该研究表明共同给予超氧化物清除剂 Tiron 后 NGF 水平降低。与奥美拉唑+Tiron 相比，硫酸镁并未进一步降低 NGF 水平。我们的结果表明，长期使用 PPI 与组织镁含量降低和心肌超氧化物产生增加有关，这加剧了梗死后的室性心律失常。镁可能是 PPI 相关梗死后心律失常的潜在靶点。
