Abstract 15826: SCUBE1 Controls BMPR2-relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a morbid vascular disease where mutations of bone morphogenetic protein receptor 2 (BMPR2) control pulmonary endothelial pathophenotypes. Transcriptomic screening from endothelial cells (ECs) derived from hereditary BMPR2-driven disease offers an opportunity to identify novel effectors in PAH pathogenesis. Methods: Public RNA-sequencing data were analyzed from inducible pluripotent stem (iPS) cell-derived endothelial cells with and without BMPR2 mutations. Candidate genes were assessed in cultured pulmonary arterial ECs (PAECs) and in rodent and human PAH. Correlations were assessed of human plasma expression with clinical disease indices. Results: Signal Peptide CUB-EGF-Domain Containing Protein 1 (SCUBE1), a putative binding partner to BMPR2, was differentially expressed in ECs carrying BMPR2 mutations. SCUBE1 was enriched in PAECs, dependent on hypoxia inducible factor-1α, and downregulated by PAH triggers, including BMPR2 knockdown, hypoxia, and IL-1β exposure. In vitro analyses defined SCUBE1 as a pathogenic effector activating BMPR2-associated SMAD1/5/9, thus regulating endothelial angiogenic potential, proliferation, and apoptosis. SCUBE1 was decreased specifically in plasma and lungs in rodents and patients with PAH but not in those with pulmonary hypertension due to left heart disease, or in the patients of other acute and chronic cardiopulmonary pathologies, including pneumonia, acute lung injury, chronic obstructive pulmonary disease, ischemic heart disease, and cardiomyopathy. An optimal plasma SCUBE1 cut point of 5.02 ng/mL was defined to diagnose PAH from control cohort with a sensitivity of 0.65 and a specificity of 0.82. In PAH patients, plasma SCUBE1 levels negatively correlated with pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular dysfunction. Conclusions: Guided by iPSC-EC sequencing, SCUBE1 was identified as a downregulated secreted factor in PAH, controlling endothelial pathophenotypes and correlated with disease indices. Clinically, SCUBE1 is a sensitive and specific PAH diagnostic marker. It may also serve as a therapeutic target given its inherent links to controlling PAH predisposition and severity.