Prostaglandin and prostaglandin receptors: present and future promising therapeutic targets for pulmonary arterial hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH), Group 1 pulmonary hypertension (PH), is a type of pulmonary vascular disease characterized by abnormal contraction and remodeling of the pulmonary arterioles, manifested by pulmonary vascular resistance (PVR) and increased pulmonary arterial pressure, eventually leading to right heart failure or even death. The mechanisms involved in this process include inflammation, vascular matrix remodeling, endothelial cell apoptosis and proliferation, vasoconstriction, vascular smooth muscle cell proliferation and hypertrophy. In this study, we review the mechanisms of action of prostaglandins and their receptors in PAH.

Main body: PAH-targeted therapies, such as endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, activators of soluble guanylate cyclase, prostacyclin, and prostacyclin analogs, improve PVR, mean pulmonary arterial pressure, and the six-minute walk distance, cardiac output and exercise capacity and are licensed for patients with PAH; however, they have not been shown to reduce mortality. Current treatments for PAH primarily focus on inhibiting excessive pulmonary vasoconstriction, however, vascular remodeling is recalcitrant to currently available therapies. Lung transplantation remains the definitive treatment for patients with PAH. Therefore, it is imperative to identify novel targets for improving pulmonary vascular remodeling in PAH. Studies have confirmed that prostaglandins and their receptors play important roles in the occurrence and development of PAH through vasoconstriction, vascular smooth muscle cell proliferation and migration, inflammation, and extracellular matrix remodeling.

Conclusion: Prostacyclin and related drugs have been used in the clinical treatment of PAH. Other prostaglandins also have the potential to treat PAH. This review provides ideas for the treatment of PAH and the discovery of new drug targets.

Keywords: Prostaglandin; Prostaglandin receptor; Pulmonary Hypertension.

Fig. 1

Hemodynamic classification and pathology of PH. The hemodynamics indices of PH include the pre-capillary PH, isolated post-capillary PH, isolated post-capillary PH, and exercise PH. Pathological changes of PH include inflammation, vascular matrix remodeling, EC apoptosis and proliferation, and VSMC proliferation and migration. Abbreviation: CO, cardiac output; Cpc PH, combined post- and pre-capillary pulmonary hypertension; ECs, endothelial cells; Ipc PH, isolated post-capillary pulmonary hypertension; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; VSMC, vascular smooth muscle cells; WU, Wood units

Fig. 2

The prostaglandin synthesis pathway and corresponding receptors. AA is released from membrane phospholipids by PLA₂, and is metabolized to PGH₂ by COX-1 and COX-2. PGH₂ is metabolized to TXA₂ by TXAS, PGI₂ by PGIS, PGE₂ by PGES, PGF_2α by PGFS, and PGD₂ by PGDS. TXA₂ binds to TP, PGI₂ binds to IP and PPARs, PGE₂ binds to EPs, PGF_2α binds to FP, and PGD₂ binds to DPs. Abbreviation: AA, arachidonic acid; COX, cyclooxygenase; CYP450, cytochrome P450; LOX, lipoxygenase; PLA₂, phospholipase A₂;

Fig. 3

Prostaglandin receptor-related pathways in alleviating pulmonary hypertension. Activation of DP1, EP2, EP4, and IP promotes vasodilation and inhibits the proliferation of pulmonary vascular smooth muscle cells (PVSMCs) through the AC/cAMP/PKA pathway. DP1 activation also attenuates hypertrophy of PVSMCs through PKA-mediated dissociation of raptor from the mTORC1 complex. EP4 also inhibits PVSMC proliferation and migration through PKA/PPARγ and Kv channels. Niacin stimulates the expression of H-PGDS in macrophages and increases the release of PGD₂. PGI₂ plays an anti-apoptotic role through PPARβ in endothelial cells and PPARα in VSMCs. Abbreviation: AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CREB, cAMP-response element binding protein; PKA, protein kinase A; PPAR, peroxisome proliferator-activated receptor

Fig. 4

How prostaglandin receptor-related pathways are involved in aggravating pulmonary hypertension. Activation of TP and EP1 promotes vasoconstriction through the PLC/PKC pathway. Via the Rho pathway, EP3 leads to extracellular matrix remodeling and TP leads to vasoconstriction. EP3 can inhibit the cAMP/PKA pathway and TP can inhibit Kv channels. CRTH2 activation in Th2 cells promotes PASMC proliferation by activating STAT6. Abbreviation: CREB, cAMP-response element binding protein; DAG, diacylglycerol; ERK: extracellular signal-regulated kinase; GEF, guanine nucleotide exchange factor; IP3, inositol triphosphate; Jak, Janus kinase; LAP: latency-associated protein; MLC: myosin light chain; MMP, Matrix metalloproteinase; MRTF-A, myocardin-related transcription factor A; MT1-MMP, membrane type 1-matrix metalloproteinase; PIP2, phosphatidylinositol (4,5) bisphosphate; PKC, protein kinase C; PLC, phospholipase C; Rock, Rho-associated protein kinase; SMAD, small mother against decapentaplegic; STAT6, signal transducer and activator of transcription 6; TGF-β1: transforming growth factor beta

Fig. 5

Prostacyclin drugs and prostaglandin receptor agonists/antagonists are involved in the pathogenesis of pulmonary arterial hypertension (PAH) through acting on distinct prostaglandin receptors. DP1 (activated by BW245C, treprostinil), EP2 (activated by butaprost, treprostinil), EP4, IP (activated by epoprostenol, beraprost, treprostinil, iloprost, selexipag) promoted vasodilation, anti-proliferation, and anti-thrombotic effects through the cAMP signaling pathway. EP1 (activated by iloprost), EP3 (activated by epoprostenol, iloprost, inhibited by L-798,106), TP (inhibited by NTP42) promoted vasoconstriction and proliferation through Rho and PKC signaling pathways. BW245C, a DP1-specific agonist; Butaprost, a highly selective EP2 receptor agonist; L-798,106, an EP3 antagonist; NTP42, a TP antagonist. Abbreviation: AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol triphosphate; PIP2, phosphatidylinositol (4,5) bisphosphate;PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C