International Union of Basic and Clinical Pharmacology: Differences and similarities between human and rodents concerning prostaglandin EP1-4 and IP receptors: Specific roles in pathophysiologic conditions

Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI(2)) and PGE(2) are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI(2) and PGE(2) exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E-2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies

Human perivascular adipose tissue dysfunction as a cause of vascular disease: Focus on vascular tone and wall remodeling

Obesity is one of the major risk factors for the development of cardiovascular diseases. It is characterized by excessive or abnormal accumulation of adipose tissue, including depots which surround the blood vessels named perivascular adipose tissue (PVAT). PVAT plays endocrine and paracrine roles by producing large numbers of metabolically vasoactive adipokines. The present review outlines our current understanding of the beneficial roles of PVAT in vascular tone and remodeling in healthy subjects supported by clinical studies, highlighting different factors or mechanisms that could mediate protective effects of PVAT on vascular function. Most studies in humans show that adiponectin is the best candidate for the advantageous effect of PVAT. However, in pathological conditions especially obesity-related cardiovascular diseases, the beneficial effects of PVAT on vascular functions are impaired and transform into detrimental roles. This change is defined as PVAT dysfunction. In the current review, the contribution of PVAT dysfunction to obesity-related cardiovascular diseases has been discussed with a focus on possible mechanisms including an imbalance between beneficial and detrimental adipokines (commonly described as decreased levels of adiponectin and increased levels of leptin or tumor necrosis factor-alpha (TNR alpha)), increased quantity of adipose tissue, inflammation, cell proliferation and endothelial dysfunction. Finally, novel pharmacotherapeutic targets for the treatment of cardiovascular and metabolic disorders are addressed. (C) 2015 Elsevier B.V. All rights reserved

The role of perivascular adipose tissue on human saphenous vein vascular tone

Perivascular adipose tissue (PVAT) is situated outside of almost every blood vessel. Recent studies showed that PVAT provides mechanical support for blood vessels and secretes vasoactive adipokines that could regulate vascular tone. However, most of the studies evaluating PVAT effects on vascular tone have been performed with vessels derived from animals. Therefore, we aimed to investigate the role of PVAT surrounding human coronary bypass graft vessels such as saphenous vein (SV). Human SV preparations were set up in an organ bath in the presence or absence of their PVAT. The presence of PVAT significantly attenuated the contractile response to prostaglandin F-2 alpha (PGF(2 alpha)). However, potassium chloride (KCI)-induced concentration-response curve wasn't modified in PVAT-intact SV preparations. On the other hand, endothelium-dependent relaxation induced by acetylcholine (ACh) or endothelium-independent relaxation induced by sodium nitroprusside (SNP) were similar between SV with PVAT versus SV without PVAT preparations. Sensitivity of the SV to contractile agonists (KCI, PGF(2 alpha)) or relaxant agonists (SNP, ACh) were not modified in the presence of PVAT. These results suggest that PVAT could decrease PGF(2 alpha)-induced contractile tone via endothelium-independent mechanisms in SV. Retaining PVAT in SV preparations during bypass graft surgery could prevent graft vasospasm possibly via PVAT derived relaxant factor(s)

Resveratrol improves high-fructose-induced vascular dysfunction in rats

High levels of fructose in the diet results in metabolic abnormalities and vascular disorders. In this study, the effect of resveratrol (RES) on vascular relaxation and contraction responses was examined in the aorta of high-fructose (HFr)-fed rats. mRNA expressions of aortic sirtuin 1 (SIRT1), GLUT5, and aldolase B were also investigated. Rats were given fructose (30%) and (or) RES (50 mg.L-1) in their drinking water for 8 weeks. In the HFr-fed rats, plasma levels of arginine and the ratio of arginine: asymmetric dimethylarginine (ADMA) decreased, whereas leptin levels increased. Decreased relaxation and increased contractile responses were detected in aortic rings. However, the aortic expressions of SIRT1, GLUT5, and aldolase B remained unchanged. RES treatment restored HFr-induced vascular dysfunction without improvements in insulin resistance. Treatment of HFr-fed rats with RES increased plasma levels of arginine and the L-arginine: ADMA ratio, and decreased plasma levels of leptin. RES increased SIRT1 expression, but decreased the expression of GLUT5 and aldolase B in aortas from HFr-fed rats. These results suggest that RES contributes to the restoration of HFr-induced vascular dysfunction in rats, at least in part, by up-regulation of SIRT 1 and down-regulation of GLUT5 and aldolase B in the aorta. Moreover, RES may have a positive influence on vasculature by partly restoring the plasma arginine: ADMA ratio and leptin levels

Downregulation of PGI(2) pathway in Pulmonary Hypertension Group-III patients

Pulmonary hypertension (PH) is a progressive and life-threating lung disorder characterized by elevated pulmonary artery pressure and vascular remodeling. PH is classified into five groups, and one of the most common and lethal forms, PH Group-III is defined as PH due to lung diseases and/or hypoxia. Due to the lack of studies in this group, PH-specific drug therapies including prostacyclin (PGI(2)) analogues have not been approved or recommended for use in these patients. PGI(2) is synthesized by the PGI(2) synthase (PGIS) enzyme, and its production is determined by measuring its stable metabolite, 6-keto-PGF1 alpha. An impaired PGI(2) pathway has been observed in PH animal models and in PH Group-I patients; however, there are contradictory results. The aim of this study is to determine whether PH Group-III is associated with altered expression of PGIS and production of PGI(2) in humans. To explore this hypothesis, we measured PGIS expression (by western blot) and PGI(2) production (by ELISA) in a large variety of preparations from the pulmonary circulation including human pulmonary artery, pulmonary vein, distal lung tissue, pulmonary artery smooth muscle cells (hPASMC), and bronchi in PH Group III (n = 35) and control patients (n = 32). Our results showed decreased PGIS expression and/or 6-keto-PGF1 alpha levels in human pulmonary artery, hPASMC, and distal lung tissue derived from PH Group-III patients. Moreover, the production of 6-keto-PGF1 alpha from hPASMC positively correlated with PGIS expression and was inversely correlated with mean pulmonary artery pressure. On the other hand, PH Group-III pulmonary veins and bronchi did not show altered PGI(2) production compared to controls. The deficit in PGIS expression and/or PGI(2) production observed in pulmonary artery and distal lung tissue in PH Group-III patients may have important implications in the pathogenesis and treatment of PH Group-III

Bronchodilation induced by PGE(2) is impaired in Group III pulmonary hypertension

Background and Purpose In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), decreased pulmonary vascular tone and tissue hypoxia is therapeutically beneficial. PGE(2) and PGI(2) induce potent relaxation of human bronchi from non-PH (control) patients via EP4 and IP receptors, respectively. However, the effects of PGE(2)/PGI(2) and their mimetics on human bronchi from PH patients are unknown. Here, we have compared relaxant effects of several PGI(2)-mimetics approved for treating PH Group I with several PGE(2)-mimetics, in bronchial preparations derived from PH Group III and control patients. Experimental Approach Relaxation of bronchial muscle was assessed in samples isolated from control and PH Group III patients. Expression of prostanoid receptors was analysed by western blot and real-time PCR, and endogenous PGE(2), PGI(2), and cAMP levels were determined by ELISA. Key Results Maximal relaxations induced by different EP4 receptor agonists (PGE(2), L-902688, and ONO-AE1-329) were decreased in human bronchi from PH patients, compared with controls. However, maximal relaxations produced by PGI(2)-mimetics (iloprost, treprostinil, and beraprost) were similar for both groups of patients. Both EP4 and IP receptor protein and mRNA expressions were significantly lower in human bronchi from PH patients. cAMP levels significantly correlated with PGI(2) but not with PGE(2) levels. Conclusion and Implications The PGI(2)-mimetics retained maximal bronchodilation in PH Group III patients, whereas bronchodilation induced by EP4 receptor agonists was decreased. Restoration of EP4 receptor expression in airways of PH Group III patients with respiratory diseases could bring additional therapeutic benefit

In search of pulmonary hypertension treatments: Effect of 17 beta-estradiol on PGI(2) pathway in human pulmonary artery

Introduction: Prostacyclin (PGI(2)) is synthetized by PGI(2) synthase (PGIS) and induces vasorelaxation via activation of cyclic AMP (cAMP) generating IP-receptor. Several components of the PGI(2) signaling pathway are reduced in patients with pulmonary hypertension (PH)

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

International audiencePulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI2) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI2 analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ETA and ETB receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI2 analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ETA/ETB receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ETB receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ETA receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control; -32±06% PH) than either agent alone. Of note, while the ETB receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI2 analogue and a selective ETA receptor antagonist

MMP-2 and -9 are decreased in varicose veins and increased in AAA.

<p>Measurement of total MMP-2 (<b>A-B</b>) and MMP-9 (<b>C-D</b>) contents in healthy saphenous veins (SV, n = 5), small and large diameter varicosities (paired SDv and LDv, n = 6), healthy aortas (HA, n = 7) and abdominal aortic aneurysms (AAA, n = 7) by EIA after 24h incubation. MMP-2 and MMP-9 contents have been normalized by tissue wet weight *P<0.05 and **P<0.01 versus respective healthy vessel.</p

Reverse regulatory pathway (H₂S / PGE₂ / MMP) in different pathologies.

<p>Reverse regulatory pathway (H₂S / PGE₂ / MMP) in different pathologies.</p