MiR-19b-1 drives gestational hypoxia-Induced pulmonary hypertension through NADPH oxidases

Gestational hypoxia can lead to intrauterine growth restriction and programming of cardiovascular diseases in adulthood via different, although not completely understood, epigenetic mechanisms. Reactive oxygen species (ROS) have been suggested to contribute to fetal programming, although their source and specific role is not well understood. We have previously shown that reactive oxygen species (ROS) derived from NADPH oxidases contribute to hypoxia induced pulmonary hypertension. However, their role in disease programming by gestational hypoxia is not resolved. We aimed to elucidate the role of NADPH oxidases and redox sensitive miRNAs in the cardiovascular response of adult offspring to transient gestational hypoxia. In this study, we demonstrate that gestational hypoxia programs pulmonary hypertension in adulthood by upregulating NADPH oxidases and downregulating miR-19b-1 subsequently affecting the mTOR pathway. Since dysregulation of miR-19b-1 induced not only pulmonary hypertension but was also associated with right ventricular pressure in congenital heart defects patients, these findings might open novel options for diagnosis, prevention and treatment of right heart disease. Wildtype mice or mice with a point mutation in the Cyba gene were mated. At E10.5, pregnant mice were exposed to 10% oxygen (Hx) in a normobaric chamber for 24 hours or kept under normoxia (Nx). From day E11.5 on, pregnant mice were kept under normoxia and allowed to deliver. Resulting offspring was kept until 10 weeks old under normoxic conditions. Heart was removed and right ventricle was separated and used for RNA isolation