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Role of the Prostanoid EP4 Receptor in Iloprost-mediated Vasodilatation in Pulmonary Hypertension

¹ University of Giessen Lung Centre, Giessen, Germany; ² Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany; ³ University of Kent, Kent Institute of Medicine and Health Sciences, Kent, United Kingdom; and ⁴ Department of Hematology and Oncology, University of Giessen, Giessen, Germany

Correspondence and requests for reprints should be addressed to Ralph Theo Schermuly, Ph.D., Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany. E-mail: ralph.schermuly{at}mpi-bn.mpg.de

Rationale: Iloprost is effective for the treatment of pulmonary hypertension. It acts through elevation of cAMP by binding to the prostacyclin receptor (IP receptor). However, there is evidence that patients with severe pulmonary hypertension have decreased expression of the IP receptor in the remodeled pulmonary arterial smooth muscle.

Objectives: We hypothesized that prostanoid receptors other than the IP receptor are involved in signal transduction by iloprost.

Methods: Immunoblotting was used to detect the IP and prostanoid EP4 receptor in lung tissue from patients with idiopathic pulmonary arterial hypertension, and immunohistochemistry was used to detect these receptors in lung sections from rats treated with monocrotaline (MCT28d). Protein and mRNA were isolated from pulmonary arterial smooth muscle cells (PASMCs) from control and MCT28d rats treated with AH6809 (an EP2 receptor antagonist) and AH23848 (an EP4 receptor antagonist) in combination with iloprost. Intracellular cAMP was also assessed in these tissues.

Measurements and Main Results: IP receptor expression was reduced in idiopathic pulmonary arterial hypertension patient lung samples and MCT28d rat lungs compared with the controls. Reverse transcriptase–polymerase chain reaction and immunoblotting of MCT28d rat PASMC extracts revealed scant expression of the IP receptor but stable expression of EP4 receptor, compared with controls. Iloprost-induced elevation in intracellular cAMP in PASMCs was dose-dependently reduced by AH23848, but not by AH6809.

Conclusions: Iloprost mediates vasodilatory functions via the EP4 receptor in the case of low IP receptor expression associated with pulmonary arterial hypertension. This is a previously unrecognized mechanism for iloprost, and illustrates that the EP4 receptor may be a novel therapeutic approach for the treatment of pulmonary arterial hypertension.

Key Words: prostanoid EP4 receptor • iloprost • pulmonary artery hypertension

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Iloprost can be effective for the treatment of pulmonary hypertension (PH), but many patients are only partially responsive to therapy. Iloprost acts through elevations of cAMP after binding to the prostacyclin receptor, but the lungs of patients with PH have decreased expression of the IP receptor. What This Study Adds to the Field Iloprost mediates vasodilatory functions via the EP4 receptor in the case of low IP receptor expression associated with pulmonary arterial hypertension. This finding indicates the EP4 receptor may be a potentially novel therapeutic target for the treatment of PH.