GPCRs in Pulmonary Arterial Smooth Muscle Cells as Novel Targets in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease that can eventually result in right heart failure and premature death. The pulmonary arterial tree in PAH narrows and limits the blood supply to the lungs, due predominately to the hyperproliferation and hyperconstriction of pulmonary artery smooth muscle cells (PASMCs). Current therapies for PAH have limited long‐term benefits (in particular, on mortality) and multiple side‐effects, including systemic hypotension. Thus, new means to target PASMCs has the potential to improve therapy for PAH. To this end, we have assessed mRNA expression of G‐protein coupled receptors (GPCRs) using Taq‐man GPCR arrays and RNA‐seq from PASMCs acquired from patients (n=4) with PAH and healthy control subjects (n=4). GPCR array analysis revealed that 91 GPCRs were expressed on average across all samples with most them shared amongst replicates (82 in control and 76 in PAH samples). Thirty‐one GPCRs, including 13 orphan GPCRs (without known physiologic agonists) were highly expressed (average delta cycle threshold < 20) across all samples. In PAH‐PASMCs, 27 and 40 GPCRs were >2‐fold more highly or lower expressed, respectively, than in control‐PASMCs. RNA‐seq analysis confirmed these results. Initial studies indicate enhanced functional activity (proliferation and signaling) of at least one of the more highly expressed GPCRs. Together, these results suggest that newly recognized, more highly expressed GPCRs in PAH‐PASMCs are potential therapeutic targets for this disease. Although further work is needed to validate such GPCRs, we propose that the use of unbiased strategies to identify GPCRs in PASMCs can provide a novel way to discover potential drivers of pathophysiology and therapeutic targets for PAH and other diseases.Support or Funding InformationSupported by Department of Defense (W81XWH‐14‐1‐0372) and the National Institutes of Health (5T32HL007444‐33)