Role of the prostanoid EP4 receptor in iloprost-mediated vasodilatation in pulmonary hypertension.
BACKGROUND
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.


OBJECTIVE
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.


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.
Lai
Ying-Ju
YJ
University of Giessen Lung Centre, Giessen, Germany.
Pullamsetti
Soni Savai
SS
Dony
Eva
E
Weissmann
Norbert
N
Butrous
Ghazwan
G
Banat
Gamal-Andre
GA
Ghofrani
Hossein Ardeschir
HA
Seeger
Werner
W
Grimminger
Friedrich
F
Schermuly
Ralph Theo
RT
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D016285:Iloprost / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction; D014665:Vasodilator Agents / Q000494:pharmacology*
C545650:PTGER4 protein, human; C545652:Ptger4 protein, rat; D044006:Receptors, Epoprostenol; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014665:Vasodilator Agents; D016285:Iloprost