Characterizations of the Right Ventricle in Ovalbumin/Sugen Model of Pulmonary Arterial Hypertension

Abstract

Right heart failure is the major cause of death among patients with pulmonary arterial hypertension (PAH). Thus, 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 pulmonary vascular remodeling. In this model, RVs of these PAH rats were hypertrophied and had severe cardiac fibrosis. No cardiac 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 a‐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 in the heart. Oxidative/nitrosative protein modifications including S‐glutathionylation, S‐nitrosylation and the 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 from the Ovalbumin/Sugen model of PAH revealed specific oxidative/nitrosative changes that are associated with RV failure.Support or Funding InformationNational Institutes of Health and National Natural Science Foundation of China