Targeting the Prostacyclin Pathway: Beyond Pulmonary Arterial Hypertension. (June 2017)

• Record Type: Journal Article
• Authors: Pluchart, Hélène; Khouri, Charles; Blaise, Sophie; Roustit, Matthieu; Cracowski, Jean-Luc
• Is Part Of: Trends in pharmacological sciences. Volume 38:Number 6(2017)
• Page Start: 512
• Page End: 523
• Publication Date: 2017-06
• Subjects: prostacyclin -- vascular homeostasis -- peroxisome proliferator-activated receptors -- multidrug resistance protein 4; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2017.03.003
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Pioneering work demonstrated that an unstable substance isolated from rabbit and pig aortas could relax arterial smooth muscle and inhibit platelet aggregation. Since then, prostacyclin (prostaglandin I2, PGI2 ) and its analogs have raised much pharmacological interest. In this review we detail how the PGI2 signaling pathway is much more complex than was initially anticipated, involving peroxisome proliferator-activated receptors (PPARs), prostaglandin transporters (PGTs), and PGI2 –thromboxane A2 (TXA2 ) receptor (IP TP) heterodimerization. We discuss the distinct affinities of PGI2 analogs for prostanoid receptors. In addition, we introduce the new direct and indirect pharmacological approaches to targeting the PGI2 pathway within the systemic circulation, including non-prostanoid agonists of the prostacyclin receptor (IP) and PGT inhibitors, as well as transcutaneous pathways using iontophoresis and nanostructured lipid carriers. Trends: PGI2 is mainly synthesized by endothelial and vascular smooth muscle cells. It exerts a variety of pharmacological effects including platelet aggregation inhibition, vasodilation, inhibition of cell adhesion, and gastroprotection. PGI2 and some of its analogs are PPARα and PPARβ/δ ligands. PGI2 may be a substrate for PGT and multidrug-resistance protein 4 (MRP4). Thus, inhibition of MRP4 and PGT could lead to higher PGI2 concentrations. Focusing development on greater specificity towards the IP receptor has led to the recent marketing of selexipag, a non-prostanoid agonist drug which metabolite MRE-269 has an increased IP receptor affinity. Microsomal prostaglandin E synthase 1 inhibition may indirectly enhance PGI2 synthesis. IP receptor variants could cause an increased risk of cardiovascular events and lead to therapeutic failure with prostacyclin analogs. PGI2 analogs can be delivered to the skin through iontophoresis or nano-structured lipid carriers. Genetically modified human mesenchymal stem cells can produce PGI2 .