Prostanoid EP? Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells.

ABSTRACT: Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP? receptor, the role of which is unknown in PAH. We hypothesised that EP? receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP? receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP? (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP? receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP? receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP? receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP? receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH.

SUBMITTER: Patel JA 

PROVIDER: S-EPMC6121445 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature