Plasma Proteomic Study in Pulmonary Arterial Hypertension Associated with Congenital Heart Diseases

Xi Zhang,Jun Wang,Qin Yang,Hai-Tao Hou,Guo-Wei He,Xiao-Cheng Liu

doi:10.1038/srep36541

Abstract

Pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) has serious consequence and plasma protein profiles in CHD-PAH are unknown. We aimed to reveal the differential plasma proteins in 272 CHD patients with or without PAH. Various types of CHD-PAH were studied. Differential plasma proteins were first detected by iTRAQ proteomic technology and those with significant clinical relevance were selected for further ELISA validation in new cohort of patients. Among the 190 differential plasma proteins detected by iTRAQ, carbamoyl-phosphate synthetase I (CPSI, related to urea cycle and endogenous nitric oxide production) and complement factor H-related protein 2 (CFHR2, related to complement system and coagulant mechanism) were selected for further ELISA validation in new cohort of 152 patients. Both CPSI and CFHR2 were down-regulated with decreased plasma levels (p < 0.01). Thus, we for the first time in CHD-PAH patients identified a large number of differential plasma proteins. The decreased CPSI expression in CHD-PAH patients may reveal a mechanism related to endogenous nitric oxide and the decrease of CFHR2 protein may demonstrate the deficiency of the immune system and coagulation mechanism. The findings may open a new direction for translational medicine in CHD-PAH with regard to the diagnosis and progress of the disease.

Highlights

Proliferation of smooth muscle cells in the small peripheral pulmonary arteries is a common characteristic in all forms of pulmonary arterial hypertension (PAH) and inflammatory mechanism seems to play an important role in certain forms of PAH3
No significant differences were present among the groups except for the age of atrial septal defect associated with pulmonary arterial hypertension (ASD-PAH) and atrial septal defect (ASD) group compared with controls in iTRAQ proteomic study (Table 1)
Similar differences of age between atrial septal defects (ASD)-PAH and Mix group existed in the enzyme-linked immunosorbent assay (ELISA) validation study (Table 2)

Summary

Introduction

Proliferation of smooth muscle cells in the small peripheral pulmonary arteries is a common characteristic in all forms of PAH and inflammatory mechanism seems to play an important role in certain forms of PAH3. In all forms of PAH, the progressive vasculopathy is a complex with a broad imbalance of vasodilators, such as nitric oxide (NO) and prostacyclin, and vasoconstrictors, such as endothelin-1 (ET-1) and thromboxane A2. This condition likely precedes the development of secondary aberrant cellular proliferation. We recently used proteomic methods to demonstrate the plasma protein changes in CHD patients[8] that may reveal the possible mechanisms for the prolonged bleeding time in patients with tetralogy of Fallot and the susceptibility to pulmonary infections in patients with CHDs. More recently, we have further reported other protein changes in CHD patients[9] with potential clinical implications. On the basis of these studies, in the present study, we used iTRAQ proteomic methods to investigate the plasma proteins from completely new group of patients with CHD-PAH and healthy controls in order to identify the differential proteins related to the pathogenesis of CHD-PAH

Objectives

Methods

Results

Conclusion