Phosphodiesterase 1C as a target for pulmonary arterial hypertension : uncovering a novel phosphodiesterase 1C-prostacyclin receptor Interaction

Pulmonary arterial hypertension (PAH) is characterised by increased pulmonary artery smooth muscle cells (PASMC) and remodelling of the pulmonary artery (PA). PAH is associated with increased phosphodiesterase 1C (PDE1C) expression and activity, which acts in part, to lower cAMP accumulation and increase proliferation of PAHPASMC. PAH-PASMC also have decreased prostacyclin (prostaglandin I2) receptor expression that limits their response to IP agonists. Recently, a PDE 1 inhibitor (16K)has been developed for central nervous system disorders. We aimed to investigate the expression and regulation of PDE1, in particular PDE1C, in models of PAH and the response of 16K, alone and together with IP receptor agonists, to provide evidencefor the therapeutic utility of PDE1 inhibitors for PAH. We hypothesise that PDE1 is a key regulator of the remodelling of the PA and PDE1 inhibitors could be repurposed for PAH. We found PDE1C expression and activity was increased with hypoxia in PASMC and PAs. PDE1 inhibition (16K) increased cAMP accumulation, induced PASMC- and PA relaxation and inhibited hypoxia-induced PASMC-proliferation. Selexipag-mediated cAMP accumulation and relaxation, which was blunted in hypoxic-PASMC and hypoxic-PAs, was restored by 16K pre-treatment; such responses were not seen withPDE5 inhibition. We found overexpression of PDE1C correlated with the increased proteasomal degradation of the IP receptor, which blunted receptor mediated responses; 16K restored the expression and function of the IP receptor via a cAMPPKA-dependent mechanism. Overexpression of other PDEs (PDE1A or 4B) were not associated with changes in IP receptor function. Of interest, removal of the PDZ motif in the IP receptor prevented the PDE1C/IP interaction. Our data show PAH is associated with increased PDE1C, which enhances IP receptor degradation and limits selexipag-dependent cAMP accumulation and PASMC relaxation. We believe repurposing PDE1 inhibitors alone, but more importantly in combination with IP-receptor agonists could offer a novel treatment approach for the management of PAH.