Abstract P3004: Small Leucine-Rich Proteoglycan Asporin Represses Smooth Muscle Cell Proliferation And Regulates Pulmonary Hypertension Development

Pulmonary arterial hypertension (PAH) is a devastating pulmonary vascular lung disease characterized by increased pressure in the pulmonary arteries leading to cardiac right ventricular (RV) hypertrophy, RV failure, and ultimately death. Current PAH therapies merely improve symptoms temporarily and patients often need lung and heart transplantation. As such, there is dire need for new insights into PAH pathophysiology to find novel therapeutic approaches. A key mechanism driving PAH is medial hyperplasia resulting from enhanced pulmonary arterial smooth muscle cell (PASMC) proliferation. Using an unbiased bioinformatics approach in an online-available microarray expression dataset of dissected pulmonary arteries (PA) from PAH patients, we discovered a novel gene, small leucine-rich proteoglycan Asporin (Aspn), which is highly and significantly upregulated in PAH compared to otherwise-healthy donor PA. Further bioinformatic analysis at a single-cell level in an online human lung dataset revealed that Aspn is most highly expressed in pulmonary SMC. We validated higher Aspn mRNA expression in human lungs and PASMC from PAH patients compared to controls, supporting our bioinformatics approach. Moreover, Aspn protein expression is elevated in PASMC in lung tissue sections from PAH patients compared to donors . Functionally, silencing Aspn in PASMC from PAH patients promoted proliferation. To find potential downstream mediators of Aspn, STRING database analysis revealed that Aspn binds to the pro-proliferative mediator TGFβ1. Accordingly, TGFβ1 downstream mediator p-SMAD2 is enhanced upon Aspn silencing in PASMC. In vivo , intratracheal delivery of Aspn siRNA in rats aggravated Sugen/Hypoxia-induced PH, as assessed by RV systolic pressure, echocardiography, and pulmonary vascular remodeling. Taken together, we hypothesize that elevated Aspn expression in PAH is a compensatory mechanism that inhibits PASMC proliferation, leading to decreased PA vascular remodeling, and that Aspn may be a novel therapeutic target against PAH.