Chronic pulmonary hypertension is characterized by vascular remodeling and perivascular inflammation. In clinical and experimental studies with inhaled or systemically-administered prostanoids, it has been shown that prostacyclin, iloprost or treprostinil reduce pulmonary arterial pressure, increase cardiac output and increase the exercise capacity. Prostacyclin and its analogs work mainly by binding to the prostacyclin receptor (IP), which belongs to the family of G-protein coupled receptors. Activation of the receptor leads to an elevation of intracellular cAMP by activation of adenylate cylase. In the first part of my thesis, the expression of the different prostanoid receptors was investigated in lungs and smooth musclecells of pulmonary hypertensive rats and lungs from patients undergoing lung transplantation due to idiopathic pulmonary arterial hypertension. Interestingly, the expression of the prostacyclin receptor was markedly reduced under the conditions of both experimental and clinical pulmonary hypertension, while other prostaglandin receptors, such as the EP4 receptor, were unchanged in their expression. In the second part, functional experiments were performed which show that iloprost and treprostinil reduce serum-induced proliferation of rat pulmonary arterial smooth muscle cells (PASMC). In addition, the iloprost-induced cAMP-production of PASMCs, but not that of treprostinil, could be blocked by the EP4 receptor antagonist AH23848, suggesting that iloprost, at least in part, acts via the EP4 receptor. An investigation was carried out on treprostinil, which is known to activate nuclear peroxisome proliferator-activated receptors (PPARs) in addition to the prostanoid receptors.Interestingly, the PPARs were downregulated in experimental and clinical pulmonary hypertension but treprostinil induced PPAR-alpha and PPAR-gamma suggesting a potential role for a prostanoid receptor-independent mechanism of treprostinil. Taken together, the prostacyclinreceptor is downregulated in experimental and clinical pulmonary hypertension and a novel role is indicated for the EP4 receptor in the signaling of iloprost, a clinically-approved prostacyclin analog. The major results of thesis were published in Am J Respir Crit Care Med.in July 2008.
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