The Role of the Cellular Communication Network Protein Family in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a complex progressive disease associated with high morbidity and mortality. Circulating serum biomarkers have the potential to optimize diagnosis and prognosis in PAH. The cellular communication network (CCN) protein family is a group of similarly structured matricellular proteins with many roles ranging from fibrosis to malignancy. Individual CCN proteins have been associated with PAH in previous studies, but no study has evaluated multiple CCN proteins as potentially relevant biomarkers in PAH. This study sought to establish associations using the circulating concentrations of measurable CCN proteins and PAH diagnosis, severity, outcomes, and other biomarkers. Serum levels of CCN1, CCN2, CCN3, and CCN6 were measured utilizing 225 patients from the PAH Biobank (PAHBiobank) with available hemodynamic data and 40 control samples. Serum levels of CCN1, 2, 3, and 6 proteins were significantly increased in PAH compared to controls. CCN1, CCN2, and CCN3 were associated with a lower 6-min walk distance. CCN2 and CCN3 were also associated with worse New York Heart Association Functional Class. Higher CCN2 and CCN3 levels correlated with higher levels of Endostatin and NT-proBNP. CCN6 was not significantly associated with any hemodynamic or clinical variables in the PAH cohort. Our results suggest that multiple CCN proteins are increased in PAH and that CCN2 and CCN3 have the most potential as novel biomarkers in PAH.