Alternative Polyadenylation and beta-adrenergic therapy in Group 3 Pulmonary Hypertension

Alternative polyadenylation (APA) is a process that has been associated with the development of Pulmonary Hypertension (PH) and lung fibrosis. APA can result in transcripts with shortened or lengthened 3'untranslated regions (UTR). Alterations to the 3'UTR landscape can have important effects on the stability and translation efficiency of mRNA. Studies in cancer, PH and lung fibrosis have demonstrated that 3'UTR shortening results in increased cell proliferation and matrix deposition, important processes in vascular remodelling, in PH. Intriguingly, our research demonstrates that pulmonary artery smooth muscle cells (PASMC) from patients with Idiopathic Pulmonary Fibrosis (IPF) and a secondary diagnosis of PH present with a unique 3'UTR signature compared to IPF (alone) or control PASMCs. Our results also demonstrate that treatment with these cells with either carvedilol, a β-adrenergic blocker or clenbuterol a β2 adrenergic agonist lead to unique changes to the 3'UTR landscape in PASMC. We next evaluated whether these agents could be beneficial in the bleomycin (BLM) model of lung fibrosis and PH. Remarkably, our results revealed that both carvedilol and clenbuterol improved right-heart function without worsening lung function. Specifically, both agents reduced right ventricle pressure and altered heart function and structure measures by echo. Taken together, these results demonstrate that despite the anti-fibrotic effect of β2-agonists, β-blockers do not worsen lung fibrosis. It is also noteworthy that drugs with opposing pharmacology were both able to improve right-heart function through a novel mechanism involving alterations in the 3'UTR signature.