Oxidative profiling of the failing right heart in rats with pulmonary hypertension.

Abstract

Right heart failure is the major cause of death among patients with pulmonary arterial hypertension (PAH). Understanding the biology of the right ventricle (RV) should help developing new therapeutic strategies. Rats subjected to the injection of Sugen5416 (an inhibitors of vascular endothelial growth factor receptor) plus the ovalbumin immunization had increased pulmonary arterial pressure and severe vascular remodeling. RVs of these rats were hypertrophied and had severe cardiac fibrosis. No apoptosis was, however, detected. Metabolomics analysis revealed that oxidized glutathione, xanthine and uric acid had increased in PAH RVs, suggesting the production of reactive oxygen species by xanthine oxidase. PAH RVs were also found to have a 30-fold lower level of α-tocopherol nicotinate, consistent with oxidative stress decreasing antioxidants and also demonstrating for the first time that the nicotinate ester of vitamin E is endogenously expressed. Oxidative/nitrosative protein modifications including S-glutathionylation, S-nitrosylation and nitrotyrosine formation, but not protein carbonylation, were found to be increased in RVs of rats with PAH. Mass spectrometry identified that S-nitrosylated proteins include heat shock protein 90 and sarcoplasmic reticulum Ca2+-ATPase. These results demonstrate that RV failure is associated with the promotion of specific oxidative and nitrosative stress.