Year-end Sale % OFF 
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 EP2 receptor, the role of which is unknown in PAH. We hypothesised that EP2 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 EP2 receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP2 (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP2 receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP2 receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP2 receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP2 receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH.
Highlights
Pulmonary arterial hypertension (PAH) is a highly proliferative, vascular remodelling disease leading to right heart failure and death, with endothelin-1 (ET-1) implicated as an important mediator of vasoconstriction and remodelling in this disease [1,2]
That other receptors might contribute to the action of treprostinil in the pulmonary vasculature, is supported by our previous work where IP receptor-independent mechanisms largely mediated the anti-proliferative effects of treprostinil in human PASMCs (HPASMCs) derived from PAH patients [16]; this occurred against a backdrop of decreased IP receptor expression
Following the identification of treprostinil as a potent activator of prostanoid EP2 receptors [13], we demonstrate for the first time using the EP2 receptor antagonist, PF-04418948 [25], as well as EP2 receptor small interfering RNAs (siRNAs), that the anti-proliferative effect of treprostinil at therapeutic doses appears largely dependent on activation of the EP2 receptor in HPASMCs from PAH patients
Summary
Pulmonary arterial hypertension (PAH) is a highly proliferative, vascular remodelling disease leading to right heart failure and death, with endothelin-1 (ET-1) implicated as an important mediator of vasoconstriction and remodelling in this disease [1,2]. Work on prostacyclin or its analogues (the prostacyclins) considered that activity at the prostanoid IP receptor significantly contributed to their pharmacological properties in humans [5], including potent vasodilator effects in the pulmonary vasculature [2,6,7] and anti-proliferative effects in distal pulmonary arterial smooth muscle cells (PASMCs) derived from normal lungs [8,9] Based on this concept, selexipag, a novel non-prostanoid and highly selective IP receptor agonist was developed for PAH [10,11] and is a clinically approved treatment [12]. That other receptors might contribute to the action of treprostinil in the pulmonary vasculature, is supported by our previous work where IP receptor-independent mechanisms largely mediated the anti-proliferative effects of treprostinil in HPASMCs derived from PAH patients [16]; this occurred against a backdrop of decreased IP receptor expression
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
