Activation of Na+-K+-ATPase with DRm217 attenuates oxidative stress-induced myocardial cell injury via closing Na+-K+-ATPase/Src/Ros amplifier.
Reduced Na+-K+-ATPase activity has close relationship with cardiomyocyte death. Reactive oxygen species (ROS) also plays an important role in cardiac cell damage. It has been proved that Na+-K+-ATPase and ROS form a feed-forward amplifier. The aim of this study was to explore whether DRm217, a proved Na+/K+-ATPase's DR-region specific monoclonal antibody and direct activator, could disrupt Na+-K+-ATPase/ROS amplifier and protect cardiac cells from ROS-induced injury. We found that DRm217 protected myocardial cells against hydrogen peroxide (H2O2)-induced cardiac cell injury and mitochondrial dysfunction. DRm217 also alleviated the effect of H2O2on inhibition of Na+-K+-ATPase activity, Na+-K+-ATPase cell surface expression, and Src phosphorylation. H2O2-treatment increased intracellular ROS, mitochondrial ROS and induced intracellular Ca2+, mitochondrial Ca2+overload. DRm217 closed Na+-K+-ATPase/ROS amplifier, alleviated Ca2+accumulation and finally inhibited ROS and mitochondrial ROS generation. These novel results may help us to understand the important role of the Na+-K+-ATPase in oxidative stress and oxidative stress-related disease.
Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, 710061, China.
Xiaofei
X
Yan
Department of Immunology and Microbiology, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
Meng
M
Xun
Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, 710061, China.
Xiaojuan
X
Dou
Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, 710061, China.
Litao
L
Wu
Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, 710061, China.
Fujun
F
Zhang
Hospital of Nephrology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. jzheng@xjtu.edu.cn.
Jin
J
Zheng
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D020013:Calcium Signaling; D002460:Cell Line; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology
D000911:Antibodies, Monoclonal; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019061:src-Family Kinases; C499075:Atp1a1 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase
DRm217; Myocardial cell injury; Na+/K+-ATPase; ROS