LAUSR

&NA; Depressed Na+/K+‐ATPase activity has long been reported to be involved in diabetic‐related cardiomyocyte death and cardiac dysfunction. However, the nature of directly regulating Na+‐K+‐ATPase in diabetic‐related myocardial diseases remains unknown. Hyperglycemia is believed as one of major factors responsible for diabetic‐related myocardial apoptosis and dysfunction. In this study, whether inhibiting Na+‐K+‐ATPase by ouabain or activating Na+‐K+‐ATPase by DRm217 has functions on high glucose (HG) ‐induced myocardial injury was investigated. Here we found that addition of DRm217 or ouabain to HG‐treated cells had opposite effects. DRm217 decreased but ouabain increased HG‐induced cell injury and apoptosis. This was mediated by changing Na+‐K+‐ATPase activity and Na+‐K+‐ATPase cell surface expression. The inhibition of Na+‐K+‐ATPase endocytosis alleviated HG‐induced ROS accumulation. Na+‐K+‐ATPase·c‐Src dependent NADPH oxidase/ROS pathway was also involved in the effects of ouabain and DRm217 on HG‐induced cell injury. These novel results may help us to understand the important role of the Na+‐K+‐ATPase in diabetic cardiovascular diseases.