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Mechanisms of Action of Inhaled Iloprost in Severe Pulmonary Hypertension - The Heart, not the Lungs

Gomez-Arroyo J, Sakagami M, Kraskauskas D, Farkas L, Byron PR, Voelkel NF.

RDD Europe 2013. Volume 1, 2013: 13-22.

Abstract:

Prostacyclin analogues, including iloprost, are broadly used to treat pulmonary arterial hypertension (PAH). While chronic prostacyclin treatment does not reverse pathologic lung vascular remodeling and only partially reduces the pulmonary arterial pressure, it does improve right ventricle (RV) function, as well as exercise capacity in PAH patients. However, the mechanisms of action of prostacyclin in PAH are still not well understood. We hypothesized that the improvement in right ventricular performance after prostacyclin treatment is induced by a direct effect of prostacyclin on the RV. To test our hypothesis, we treated rats with established severe PAH and RV dysfunction with the synthetic analogue of prostacyclin PGI2, iloprost, with a dosing regimen similar to that used in patients with PAH. Iloprost-treated rats demonstrated a substantial improvement in exercise endurance, and significant improvement in cardiac output and RV longitudinal contraction; however there were no changes in pulmonary artery pressure and lung vascular remodeling compared to drug-free vehicle controls. The improvement in RV function was associated with decreased RV myocardial fibrosis and decreased RV collagen synthesis. The expression of connective tissue growth factor (CTGF) in RV tissue showed a 20-fold decrease after inhaled iloprost treatment. In vitro, primary human cardiac fibroblasts, concomitantly treated with recombinant human TGF-β1 and iloprost, demonstrated a similar downregulation of CTGF expression. Iloprost also reduced phophorylated-ERK protein levels in rat RV tissue. Iloprost signals via the cAMP/protein kinase A pathway and its effect on CTGF expression could be blocked by a protein kinase A inhibitor. Finally, we demonstrate that iloprost treatment prevented TGF-β-induced fibroblast activation. Overall, our results indicate that inhaled iloprost has direct cardiac effects, improves RV function and reverses established fibrosis, partially by preventing TGF-β-induced fibroblast activation and by reducing CTGF expression and collagen synthesis.