Proteomic Study Reveals Altered Carbamyl‐phosphate Synthetase I in Congenital Heart Disease‐associated Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) associated with congenital heart disease and left‐to‐right shunt is characterized by increased pulmonary vascular resistance and remodeling. Endogenous nitric oxide (NO) derived from arginine supplied by the urea cycle is critical for the maintenance of normal pulmonary arterial pressure. The rate‐limiting step in the urea cycle is catalyzed by a mitochondrial enzyme, carbamoyl‐phosphate synthetase I (CPSI). We examined the hypothesis that CPSI may be associated with PAH by an proteomic method using iTRAQ to compare protein profiles in pooled plasma samples of ventricular septal defect (VSD) patients with PAH (VSD‐PAH), VSD, and normal controls (n=20 for each). Among more than 150 differential plasma proteins, CPSI was 2‐fold down‐regulated in VSD‐PAH. We further validated CPSI in new VSD‐PAH and VSD patients as well as controls by ELISA. The plasma CPSI level in VSD‐PAH (109.2±7.718 pg/ml, N=40) was significantly lower (P<0.01) than that in VSD (196.5±35.68 pg/ml, N=21) and normal controls (431.8±41.42 pg/ml, N=37, p<0.0001). Thus we have for the first time identified alterations of the mitochondrial enzyme CPSI in the plasma of VSD‐PAH patients, suggesting important role of the urea cycle‐arginine‐NO pathway in PAH and providing important information for biomarkers in PAH and possible future interventional strategy.Supported by NSFC 81170148, China Postdoc Sci Foundation 2014M561181, National S & T Major Project 2013ZX09303004‐005.