Targeting the Prostacyclin Pathway: Beyond Pulmonary Arterial Hypertension

前列环素 前列腺素 前列腺素 受体 药理学 血栓素A2 血栓素 血栓素受体 化学 脂质信号 血小板 医学 内科学 生物化学
作者
Hélène Pluchart,Charles Khouri,S. Blaise,Matthieu Roustit,Jean‐Luc Cracowski
出处
期刊:Trends in Pharmacological Sciences [Elsevier BV]
卷期号:38 (6): 512-523 被引量:54
标识
DOI:10.1016/j.tips.2017.03.003
摘要

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. 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. 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. deletion of individual cells by fragmentation into membrane-bound particles which are phagocytosed by other cells. the proportion of the administered dose that is absorbed into the bloodstream. diffusible factors causing smooth muscle hyperpolarization and thus vasodilation. It should be distinguished from the spread of hyperpolarizing current from the endothelium to the vascular smooth muscle, termed endothelium-dependent hyperpolarization. an enzyme in endothelial cells that catalyzes the reaction of L-arginine with 2 O2 and 1.5 NADPH to form NO, L-citrulline, 1.5 NADP+, and 2 H2O. method for transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current. It is non-invasive and has several advantages compared to passive transdermal administration, such as faster drug release and better control of the dose delivered. Factors involved in iontophoretic transfer include the concentration and the size of the molecule, the proportion ionized, the intensity of the current, whether it is continuous or discontinuous, and its duration. The nature of the skin surface (thickness, glabrous or not) and its integrity also play key roles. lipid particles produced by mixing solid and liquid lipids that become solid but do not crystallize, with dimensions of <100 nm. a gaseous mediator of cell-to-cell communication and a potent vasodilator formed from L-arginine in bone, brain, endothelium, granulocytes, pancreatic β cells, and peripheral nerves by constitutive NOS, and in hepatocytes, Kupffer cells, macrophages, and smooth muscle by inducible NOS. NO activates guanylate cyclase, mediates penile erection, and may be the first known retrograde neurotransmitter. relating to a type of hormone function in which the effects of the hormone are restricted to the local environment. a family of transcription factors that recognize response elements in the promoters of their target genes. Three main isoforms exist (PPARα, PPARβ/δ, PPARγ) and may be activated by a wide variety of endogenous or exogenous ligands. also known as prostaglandin I2, the molecule has a short half-life (4 minutes) and is produced by the endothelium. It acts as a physiological antagonist of TXA2. Epoprostenol is a synthetic PGI2 molecule used as a drug for pulmonary arterial hypertension (PAH). physiologically active and ubiquitously produced lipid compounds derived from fatty acids; contain 20 carbon atoms including a five-carbon ring. a key enzyme in PG biosynthesis that converts arachidonic acid into PGH2 in a two-step process that combines endoperoxide activity and peroxidase activity. cyclic lipid mediators that arise from enzymatic cyclo-oxygenation of linear polyunsaturated fatty acids. Active prostanoids derived from arachidonic acid (AA) include PGs and thromboxane A2 (TXA2).
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