Stabilization of Hypoxia-inducible Factor by DMOG Inhibits Development of Chronic Hypoxia-Induced Right Ventricular Remodeling

Background:One important determinant of longevity in congenital heart disease is right ventricular (RV) function, and this is especially true in cyanotic congenital heart disease. However, there is a paucity of data concerning right ventricular remodeling (RVR) in the setting of chronic hypoxia. Dimethyloxalylglycine (DMOG) is a competitive inhibitor of hypoxia-inducible factor (HIF)-hydroxylated prolyl hydroxylase and has been shown to play an important role against ischemia-reperfusion myocardial injury.Methods:We tested the hypothesis that DMOG prevents the development RVR after chronic hypoxia exposure. Rats were injected with saline or DMOG and exposed to room air or continued hypoxia for 4 weeks. In addition, we explored the response of myocardial erythropoietin and its receptor to hypoxic exposure.Results:Treatment with DMOG attenuated myocardial fibrosis, apoptosis, and oxidative stress, which lead to enhanced RV contractile function. As an endpoint of HIF-dependent cardioprotection, a novel pathway in which nuclear factor kappa B links HIF-1 transcription was defined.Conclusions:This study supports a role for HIF-1 stabilizers in the treatment of RVR and brings into question the commonly held concept that RVR follows a linear relationship with increased RV afterload.