H + /K + -ATPase-Inhibition Causes Left–Right Aortic Arch Inversion in Mouse Development

Abstract

An organ known as a “node” forms during embryogenesis and plays a vital role in determining laterality in vertebrates. However, according to some reports in vertebrates, left–right patterning may be determined long before the node has developed. In this study, we analyzed left–right asymmetry formation in mammals based on ion-signaling factors, which has never been attempted before. First, a proton pump inhibitor was injected into pregnant mice to investigate whether H⁺/K⁺-ATPase is involved in the differentiation of pharyngeal arch arteries during embryonic development. Injection of 30 mg/kg of lansoprazole early in the organogenesis period increased the penetrance of right aortic arch formation by 34% compared to a saline injection. Furthermore, administration of a proton pump inhibitor resulted in strong expression of PI3K/phosphor-AKT, which led to potent inhibition of apoptosis induction factors such as BAD. This could relate to why the right pharyngeal arch arteries, which should have disappeared during differentiation, remained intact. The other important point is that proton pump inhibitors suppressed calcineurin signaling, and Wnt5a expression was significantly higher than in the controls. This research is particularly notable for demonstrating that administration of an H⁺/K⁺-ATPase inhibitor could cause dextroposition of the fetal vasculature. Moreover, since previous publications have reported that H⁺/K⁺-ATPase plays a role in asymmetry in other species, this article adds important information for developmental biology in that the role of H⁺/K⁺-ATPase in asymmetry is conserved in the mouse model, suggesting that rodents are not unique and that a common mechanism may function across vertebrates.