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.
Center of Pediatric Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Sen
S
Zhang
Kai
K
Ma
Yiwei
Y
Liu
Xiangbin
X
Pan
Qiuming
Q
Chen
Lei
L
Qi
Shoujun
S
Li
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002908:Chronic Disease; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016278:Ventricular Function, Right / Q000187:drug effects* / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D000600:Amino Acids, Dicarboxylic; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C040947:oxalylglycine