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

Lai, Ying‐Ju; Pullamsetti, Soni Savai; Dony, Eva; Weißmann, Norbert; Butrous, Ghazwan; Banat, Gamal-Andre; Ghofrani, Hossein Ardeschir; Seeger, Werner; Grimminger, Friedrich; Schermuly, Ralph Theo

doi:10.1164/rccm.200710-1519oc

Cited by 76 publications

(88 citation statements)

References 49 publications

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“…We found that IP receptor mRNA and protein levels were reduced in PASMCs from patients with IPAH, consistent with recent studies showing IP receptor loss in whole lungs from patients with IPAH and in rats after monocrotaline treatment (12). Furthermore, intimal proliferating cells of distal vessels stained weakly for the IP receptor, which agrees with reports of decreased expression of prostacyclin synthase in small pulmonary arterial vessels in IPAH and its absence in concentric plexiform lesions (19).…”

Section: Role Of the Ip Receptor In Ipahsupporting

confidence: 92%

“…PASMCs from patients with IPAH would fail to respond normally because IP receptor density had decreased (12), because the receptor had become dysfunctional, or both. Reduced expression of PPARg, reported in adult IPAH lungs (13), might also reduce prostacyclin analog signaling through this pathway.…”

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

“…That iloprost (and to a lesser extent prostacyclin) can bind to contractile EP 1 and EP 3 receptors with a similar potency to IP receptors (8,9) suggests that tachyphylaxis to these agents may be accentuated in IPAH. Alternatively, loss of the IP receptor may drive prostacyclin analogs to signal through other Gscoupled prostanoid receptors, including EP 4 for iloprost (12) and EP 2 for treprostinil (28). Thus, the possibility that these receptors contribute analog effects in IPAH cells cannot be excluded.…”

Section: Role Of the Ip Receptor In Ipahmentioning

confidence: 99%

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Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

Falcetti¹,

Hall²,

Phillips³

et al. 2010

Am J Respir Crit Care Med

118

127

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Rationale: Prostacyclin analogs, used to treat idiopathic pulmonary arterial hypertension (IPAH), are assumed to work through prostacyclin (IP) receptors linked to cyclic AMP (cAMP) generation, although the potential to signal through peroxisome proliferatoractivated receptor-g (PPARg) exists. Objectives: IP receptor and PPARg expression may be depressed in IPAH. We wished to determine if pathways remain functional and if analogs continue to inhibit smooth muscle proliferation. Methods: We used Western blotting to determine IP receptor expression in peripheral pulmonary arterial smooth muscle cells (PASMCs) from normal and IPAH lungs and immunohistochemistry to evaluate IP receptor and PPARg expression in distal arteries. Measurements and Main Results: Cell proliferation and cAMP assays assessed analog responses in human and mouse PASMCs and HEK-293 cells. Proliferative rates of IPAH cells were greater than normal human PASMCs. IP receptor protein levels were lower in PASMCs from patients with IPAH, but treprostinil reduced replication and treprostinil-induced cAMP elevation appeared normal. Responses to prostacyclin analogs were largely dependent on the IP receptor and cAMP in normal PASMCs, although in IP 2/2 receptor cells analogs inhibited growth in a cAMP-independent, PPARg-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARg agonist and inhibited (z 60%) by the PPARg antagonist GW9662. This coincided with increased PPARg expression in the medial layer of acinar arteries. Conclusions: The antiproliferative effects of prostacyclin analogs are preserved in IPAH despite IP receptor down-regulation and abnormal coupling. PPARg may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.

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Section: Role Of the Ip Receptor In Ipahsupporting

confidence: 92%

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

Section: Role Of the Ip Receptor In Ipahmentioning

confidence: 99%

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Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

Falcetti¹,

Hall²,

Phillips³

et al. 2010

Am J Respir Crit Care Med

118

127

View full text Add to dashboard Cite

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“…PGI 2 analogs are available in different formulations and are potent ligands with different binding affinities for the various prostanoid receptors. Ioprost was reported with affinity to the IP, EP1, EP2, EP3 and EP4 receptors, and treprostinil was reported with affinity to the IP and EP2 receptors (34)(35)(36). The physiological activities of the analogs depend on the receptor they activate, and these effects can be receptor-specific.…”

Section: Discussionmentioning

confidence: 99%

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

Kuo

Lin

Yang

et al. 2011

Mol Med

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“…Prostanoids remain a mainstay for the treatment of PAH and are currently in clinical trial as part of a combinatorial therapy with treatments such as sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The discovery of sildenafil as a therapeutic strat- Gust and Schuster, 2001;Lai et al, 2008;Mouchaers et al, 2009;Obata et al, 2008;van Albada et al, 2006 Monocrotaline + pneumonectomy Zhao et al, 2001). Combinations of sildenafil with the HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor, statins (e.g.…”

Section: What Constitutes a Good Model Of Pah?mentioning

confidence: 99%

Idiopathic pulmonary arterial hypertension

Firth

Mandel

Yuan

2010

Disease Models &Amp; Mechanisms

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Despite improved understanding of the pathobiology of pulmonary arterial hypertension (PAH), it remains a severe and progressive disease, usually culminating in right heart failure, significant morbidity and early mortality. Over the last decade, some major advances have led to substantial improvements in the management of PAH. Much of this progress was pioneered by work in animal models. Although none of the current animal models of pulmonary hypertension (PH) completely recapitulate the human disease, they do provide insight into the cellular pathways contributing to its development and progression. There is hope that future work in model organisms will help to define its underlying cause(s), identify risk factors and lead to better treatment of the currently irreversible damage that results in the lungs of afflicted patients. However, the difficulty in defining the etiology of idiopathic PAH (IPAH, previously known as primary pulmonary hypertension) makes this subset of the disease particularly difficult to model. Although there are some valuable existing models that are relevant for IPAH research, the area would value from the development of new models that more closely mimic the clinical pathophysiology of IPAH.

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

Cited by 76 publications

References 49 publications

Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

Idiopathic pulmonary arterial hypertension

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