Proton Pump Inhibition Impairs Ventricular Remodeling in Infarcted Rats: Role of Superoxide‐DDAH Axis

Abstract

Proton pump inhibitors (PPIs) were frequently used for preventing or treating peptic ulcer. Recently, PPIs have been shown to increase the risk of myocardial infarction. The purpose of this study was to determine whether PPIs adversely affect ventricular remodeling in infarcted rats. Male Wistar rats were randomly assigned into either vehicle, omeprazole, omeprazole + vitamin C, omeprazole + olmesartan, or famotidine for 4 weeks starting 24 hours after ligation. Compared with vehicle‐treated infarcted rats, omeprazole‐treated infarcted rats had significant changes with reduced myocardial vitamin C levels, increased oxidant production, and decreased dimethylarginine dimethylaminohydrolase 2 (DDAH2) activity, which in turn increased asymmetric dimethylarginine (ADMA) levels and impaired ventricular remodeling. These changes were prevented by treatment with either vitamin C or olmesartan. For gastric protection similar to omeprazole, the H2 blocker famotidine had no effect on ventricular remodeling. In contrast to the in vivo results, the ex vivo study to show similar superoxide and DDAH2 protein levels between vehicle‐ and omeprazole‐treated infarcted rats suggested involvement of gastric vitamin C uptake in mediating the impaired axis of vitamin C‐superoxide‐DDAH2 in the in vivo measurement. Administration of PPI was associated with impaired DDAH2 expression and increased myocardial ADMA by reduced gastric vitamin C uptake, which impaired ventricular remodeling after infarction. These effects are prevented by coadministering vitamin C or olmesartan. Our results indicate that the superoxide‐DDAH2 axis could be a potential target for the treatment of ventricular remodeling.Support or Funding InformationThis work was supported by the grants of An‐Nan Hospital (ANHRF 104‐02), China Medical University (CMU103‐S‐07) and Ministry of Science and Technology (MOST 104‐2314‐B‐039‐021), Taiwan.