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

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 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.

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

“…We found no evidence of reparative remodelling toward a normal arterial architecture in these children, and smooth muscle cells derived from three of the treated children reported here have, in vitro, abnormally high replication rates [46]. The extent to which the drugs directly affect the vasculature is uncertain.…”

The challenge of managing pulmonary arterial hypertension in adults with congenital heart disease

“…Prostacyclin is produced by cyclooxygenase-1 and prostacyclin synthase from arachidonic acid cleaved from membrane-bound lipids by phospholipase A2. Activation of prostacyclin receptors on smooth muscle cells leads to the stimulation of adenylate cyclase, increasing cellular cAMP levels [25]. This in turn induces vasodilation and inhibits cellular proliferation.…”

Advances in the Management of Pediatric Pulmonary Hypertension

“…[332][333][334][335] In an interesting recent study, Falcetti and colleagues demonstrated that PPAR␥ expression was enhanced in the medial layer of arteries from patients with idiopathic PH, compared to controls. 322 Whether that finding conflicts with the previous description of decreased lung tissue expression in advanced PH is unclear, since the initial study did not quantitate expression in the medial muscle layers. 321 Moreover, those investigators demonstrated that the PPAR␥ agonist rosiglitazone potentiated, and PPAR␥ antagonism inhibited, the anti-proliferative effects of treprostinil in pulmonary artery smooth-muscle cells, whereas down-regulation of the IP receptor had no effect.…”

“…320 Although investigations of the vasculature have focused primarily on the systemic circulation, one study showed that PPAR gamma (PPAR␥), one of the 3 PPAR subclasses, was decreased in lung tissue taken from patients with severe PAH. 321,322 Subsequently, increasing efforts have been made to evaluate PPAR␥ as a therapy for PH. Indeed, studies have identified interactions between PPAR␥ and multiple mediators that are important in the pathogenesis of pulmonary vascular disease, including nitric oxide, ET-1, PGI 2 , ROCK, EPCs, asymmetric dimethylarginine, insulin, oxidative stress, and the BMPR2 pathway.…”

“…Indeed, studies have identified interactions between PPAR␥ and multiple mediators that are important in the pathogenesis of pulmonary vascular disease, including nitric oxide, ET-1, PGI 2 , ROCK, EPCs, asymmetric dimethylarginine, insulin, oxidative stress, and the BMPR2 pathway. [322][323][324][325][326][327][328][329][330][331] PPAR␥ expression was decreased in several studies that used rodent models of PH, and PPAR␥ agonist treatment attenuated pulmonary vascular remodeling. [332][333][334][335] In an interesting recent study, Falcetti and colleagues demonstrated that PPAR␥ expression was enhanced in the medial layer of arteries from patients with idiopathic PH, compared to controls.…”