As in humans and other
As in humans and other mammalians spontaneous activity of sinoatrial pacemaker Bedaquiline in in the zebrafish heart crucially depends on proper HCN4 channel activity (If) and spontaneous diastolic depolarization [15,81]. Whether Na+/K+-ATPase currents regulate next to phase of myocardial repolarization also If and consequently spontaneous diastolic depolarization is largely unknown and should be further investigated.
Conclusion Recent genetic studies could show that bradycardia can be associated with mutations in various genes of ion channels and modifier genes [2,82]. However, in most patients suffering from severe bradycardia the underlying genetic and molecular pathology remains unclear. Using the bradycardic zebrafish mutant line hiphop, we demonstrated here for the first time in a genetic in vivo model that reduced Na+/K+-ATPase function reproduce a severe bradycardia phenotype via prolonged myocardial repolarization. Accordingly, genome-wide association studies in humans demonstrated that single nucleotide polymorphisms (SNP) in Na+/K+ATPase are associated with long QT interval [24,83]. Based on these findings, screening for genetic variants in Na+/K+-ATPase in patients with long QT syndrome as well as severe bradycardia might help to further dissect the pathomechanisms of these clinical important cardiac arrhythmias. The following are the supplementary data related to this article.
Sources of funding This work was supported by the Deutsche Forschungsgemeinschaft (DFG) RO2173/2-3, RO2173/3-2, JU2859/2-1 and the Bundesministerium für Bildung und Forschung01GS1104 (NGFNplus), 01KU0901C (Insight-DCM), 01ZX1407A (e:Med-Symbol-HF). Alexander Pott was supported by a Research Grant of the Clinician Scientist Program of the University Medical School Ulm. Susanne Rinné was supported by a Research Grant of the University Medical Center Giessen and Marburg (UKGM).
Introduction The Na+- and K+-dependent adenosine triphosphatase (Na+-K+-ATPase) is a traditional ion pump which resides in cell membrane. It transports Na+ out and K+ into the cell for maintaining cell membrane potential and electrochemical gradient. Na+-K+-ATPase is a key enzyme in human cardiac myocytes (Schwinger et al., 2003). For centuries, digitalis was used in the treatment of heart failure and atrial arrhythmia by inhibiting the ion-pumping function of Na+-K+-ATPase (Rahimtoola, 2004). However, recent evidences indicated that Na+-K+-ATPase had function on cardiac cell death, apoptosis and hypertrophy (Liu et al., 2016; Sapia et al., 2010). Ischemia/reperfusion (IR) injury is the major pathological process in ischemic heart disease such as myocardial infarction. Many studies have shown that the reduction of Na+-K+-ATPase activity has close relationship with IR-related cardiomyocyte death and dysfunction (Guo et al., 2011; Hilgemann et al., 2006). For example, Na+-K+-ATPase activity and membrane expression were decreased in IR-stimulated myocardial cells and hearts (Takata et al., 2013; Guo et al., 2015). In return, drug treatment that alleviated IR-related cardiac cell injury was often accompanied by the increase of Na+-K+-ATPase activity (Chen et al., 2016; Huang et al., 2015). This prompts us to investigate whether activation of Na+-K+-ATPase could protect cardiac cells from IR injury. Na+-K+-ATPase consists α and ß two subunits. DR region (897DVEDSYGQQWTYEQR911 in α1-subunit) has been demonstrated as an active site of Na+-K+-ATPase (Xu, 2005). Xu and Zheng both reported that activation of Na+-K+-ATPase with DR region specific antibody strengthened heart contraction and alleviated myocardial injury (Xu, 2005; Xu et al., 2006; Zheng et al., 2011). DRm217, a DR-region-specific monoclonal antibody, can bind to Na+-K+-ATPase specifically (Yan et al., 2016). In previous, we had observed that DRm217 increased Na+-K+-ATPase activity and decreased reactive oxygen species (ROS) accumulation (Yan et al., 2016; Yan et al., 2017). In present, we aimed to detect whether DRm217 could protect cardiac cell against IR injury and reveal the potential mechanism under it.