Sen Zhang1, Kai Ma, Yiwei Liu, Xiangbin Pan, Qiuming Chen, Lei Qi, Shoujun Li. 1. Center of Pediatric Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Abstract
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.
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.