Abstract
Previous studies have shown that the activity and expression of Na+/K+-ATPase (NKA) are down-regulated in the failing hearts, and that an antibody against the DR-region of NKA (DR-Ab) can stimulate its activity. The present study was designed to investigate the beneficial effects of this antibody against cardiac injury and the underlying mechanisms. We found that DR-Ab improved cardiac function, alleviated cardiac hypertrophy and reduced oxidative stress in isoproterenol-treated mice. In AC16 human cardiomyocytes, DR-Ab increased cell viability and attenuated apoptosis under oxidative stress. Corresponding to the observation of reduced NKA activity, NKA abundance on plasma membrane was lowered during oxidative stress. Suppressed activity of protein phosphatase 2 A (PP2A) was responsible for the loss of membrane NKA due to the increased phosphorylation of key serine residues that trigger endocytosis. Incubation with DR-Ab restored PP2A activity and stabilized NKA expression on the plasma membrane. Inhibitors of PP2A abolished the protective effect of DR-Ab against oxidative stress. In summary, our data indicate that loss of membrane NKA may contribute to cardiac pathologies in heart failure. DR-Ab, by stabilizing membrane NKA, protects cardiomyocytes against oxidative injury and improves cardiac function in the failing hearts, suggesting a novel approach to treat heart failure.
Highlights
In spite of the advancing knowledge in cardiac pathologies over the years, cardiovascular diseases remain a major cause of mortality and morbidity worldwide[1,2]
We found that the same antibody confers cardioprotection against ischemic injury in both rat cardiomyocytes and isolated hearts, probably via the activation of PI3K/Akt/ERK pathway[12]
DR-Ab was purified with a protein A/G resin column and the titer was determined by ELISA against
Summary
In spite of the advancing knowledge in cardiac pathologies over the years, cardiovascular diseases remain a major cause of mortality and morbidity worldwide[1,2]. Reactive oxygen species (ROS) are increased in various heart diseases including myocardial infarction, ischemia/reperfusion injury, hypertrophy and heart failure. ROS activate pathological responses including reprogramming of gene expression, and an increase in protein synthesis[4]. The Na+/K+-ATPase (NKA) is a ubiquitously expressed transmembrane protein that actively exchanges three Na+ out of and two K+ into cells[5]. This process is responsible for maintaining the electrochemical gradient, and the membrane potential, of the cell membrane. Decreased NKA activity and expression have long been associated with heart failure in both animal models[7] and human patients[8,9,10]. To examine whether the protective effect of DR-Ab in failing hearts is mediated by maintaining functional NKA under oxidative stress and its molecular mechanisms
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