FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing of pulmonary arteries, resulting in right heart failureand death. BMPR2( bone morphogenetic protein receptortype 2) mutations account for most familial PAH forms whereas reduced BMPR2is present in many idiopathic PAH forms, suggesting dysfunctional BMPR2signaling to be a key feature of PAH. Modulating BMPR2signaling is therapeutically promising, yet how BMPR2is downregulated in PAH is unclear.Objectives: We intended to identify and pharmaceutically target BMPR2modifier genes to improve PAH.Methods: We combined siRNA high-throughput screeningof >20,000 genes with a multicohort analysis of publicly available PAH RNA expression data to identify clinically relevant BMPR2modifiers. After confirming gene dysregulation in tissue from patients with PAH, we determined the functional roles of BMPR2modifiers in vitro and tested the repurposeddrug enzastaurinfor its propensity to improve experimental pulmonary hyper...