Smooth muscle proliferation and role of the prostacyclin (IP) receptor in idiopathic pulmonary arterial hypertension.

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Falcetti E, Hall SM, Phillips PG, Patel J, Morrell NW, Haworth SG, Clapp LH

Smooth muscle proliferation and role of the prostacyclin (IP) receptor in idiopathic pulmonary arterial hypertension.

Am J Respir Crit Care Med. 2010 Nov 1;182(9):1161-70. doi: 10.1164/rccm.201001-0011OC. Epub 2010 Jul 9.

PubMed ID

20622039 [ View in PubMed

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Abstract

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 proliferator-activated receptor-gamma (PPARgamma) exists. OBJECTIVES: IP receptor and PPARgamma 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 PPARgamma 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(-/-) receptor cells analogs inhibited growth in a cAMP-independent, PPARgamma-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARgamma agonist and inhibited ( approximately 60%) by the PPARgamma antagonist GW9662. This coincided with increased PPARgamma 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. PPARgamma may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Treprostinil	Prostacyclin receptor	Protein	Humans	Yes	Agonist	Details