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2.
Br J Pharmacol ; 177(1): 161-174, 2020 01.
Article in English | MEDLINE | ID: mdl-31476020

ABSTRACT

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. PGE2 and PGI2 induce potent relaxation of human bronchi from non-PH (control) patients via EP4 and IP receptors, respectively. However, the effects of PGE2 /PGI2 and their mimetics on human bronchi from PH patients are unknown. Here, we have compared relaxant effects of several PGI2 -mimetics approved for treating PH Group I with several PGE2 -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 PGE2 , PGI2 , and cAMP levels were determined by ELISA. KEY RESULTS: Maximal relaxations induced by different EP4 receptor agonists (PGE2 , L-902688, and ONO-AE1-329) were decreased in human bronchi from PH patients, compared with controls. However, maximal relaxations produced by PGI2 -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 PGI2 but not with PGE2 levels. CONCLUSION AND IMPLICATIONS: The PGI2 -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.


Subject(s)
Bronchi/metabolism , Bronchodilator Agents/metabolism , Bronchodilator Agents/therapeutic use , Dinoprostone/metabolism , Dinoprostone/therapeutic use , Hypertension, Pulmonary/metabolism , Adult , Aged , Aged, 80 and over , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Bronchi/drug effects , Bronchi/pathology , Bronchodilator Agents/pharmacology , Dinoprostone/pharmacology , Dose-Response Relationship, Drug , Epoprostenol/analogs & derivatives , Epoprostenol/metabolism , Epoprostenol/pharmacology , Epoprostenol/therapeutic use , Female , Humans , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/pathology , Iloprost/metabolism , Iloprost/pharmacology , Iloprost/therapeutic use , Male , Middle Aged , Organ Culture Techniques , Pyrrolidinones/metabolism , Pyrrolidinones/pharmacology , Pyrrolidinones/therapeutic use , Receptors, Prostaglandin E, EP4 Subtype/agonists , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Tetrazoles/metabolism , Tetrazoles/pharmacology , Tetrazoles/therapeutic use , Vasodilator Agents/metabolism , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use , Young Adult
3.
Cardiovasc Res ; 114(4): 540-550, 2018 03 15.
Article in English | MEDLINE | ID: mdl-29385543

ABSTRACT

Current knowledge suggests that intimal smooth muscle cells (SMCs) in native atherosclerotic plaque derive mainly from the medial arterial layer. During this process, SMCs undergo complex structural and functional changes giving rise to a broad spectrum of phenotypes. Classically, intimal SMCs are described as dedifferentiated/synthetic SMCs, a phenotype characterized by reduced expression of contractile proteins. Intimal SMCs are considered to have a beneficial role by contributing to the fibrous cap and thereby stabilizing atherosclerotic plaque. However, intimal SMCs can lose their properties to such an extent that they become hard to identify, contribute significantly to the foam cell population, and acquire inflammatory-like cell features. This review highlights mechanisms of SMC plasticity in different stages of native atherosclerotic plaque formation, their potential for monoclonal or oligoclonal expansion, as well as recent findings demonstrating the underestimated deleterious role of SMCs in this disease.


Subject(s)
Atherosclerosis/pathology , Cell Dedifferentiation , Cell Lineage , Cell Plasticity , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/pathology , Plaque, Atherosclerotic , Animals , Arteries/metabolism , Arteries/pathology , Arteries/physiopathology , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/physiopathology , Epigenesis, Genetic , Fibrosis , Foam Cells/metabolism , Foam Cells/pathology , Humans , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/physiopathology , Myocytes, Smooth Muscle/metabolism , Phenotype , Signal Transduction , Transcription, Genetic , Vasoconstriction
4.
Cardiovasc Pathol ; 32: 15-25, 2018.
Article in English | MEDLINE | ID: mdl-29149696

ABSTRACT

Plasminogen is a circulating zymogen which enters the arterial wall by radial, transmural hydraulic conductance, where it is converted to plasmin by tissue plasminogen activator t-PA on an activation platform involving S100A4 on the vascular smooth muscle cell (vSMC) membrane. Plasmin is involved in the progression of human thoracic aneurysm of the ascending aorta (TAA). vSMCs protect the TAA wall from plasmin-induced proteolytic injury by expressing high levels of antiproteases. Protease nexin-1 (PN-1) is a tissue antiprotease belonging to the serpin superfamily, expressed in the vascular wall, and is able to form a covalent complex with plasmin. LDL receptor-related protein-1 (LRP-1) is a scavenger receptor implicated in protease-antiprotease complex internalization. In this study, we investigated whether PN-1 and LRP-1 are involved in the inhibition and clearance of plasminogen by the SMCs of human TAA. We demonstrated an overexpression of S100A4, PN-1, and LRP-1 in the medial layer of human TAA. Plasminogen activation taking place in the media of TAA was revealed by immunohistochemical staining and plasmin activity analyses. We showed by cell biology studies that plasmin-PN-1 complexes are internalized via LRP-1 in vSMCs from healthy and TAA media. Thus, two complementary mechanisms are involved in the protective role of PN-1 in human TAA: one involving plasmin inhibition and the other involving tissue clearance of plasmin-PN1 complexes via the scavenger receptor LRP-1.


Subject(s)
Aorta/pathology , Aortic Aneurysm, Thoracic/pathology , Fibrinolysin/metabolism , Muscle, Smooth, Vascular/metabolism , Serpin E2/metabolism , Adult , Aorta/metabolism , Aortic Aneurysm, Thoracic/metabolism , Female , Humans , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Male , Middle Aged
5.
Front Physiol ; 7: 273, 2016.
Article in English | MEDLINE | ID: mdl-27445860

ABSTRACT

Zymogens are delivered to the arterial wall by radial transmural convection. Plasminogen can be activated within the arterial wall to produce plasmin, which is involved in evolution of the atherosclerotic plaque. Vascular smooth muscle cells (vSMCs) protect the vessels from proteolytic injury due to atherosclerosis development by highly expressing endocytic LDL receptor-related protein-1 (LRP-1), and by producing anti-proteases, such as Protease Nexin-1 (PN-1). PN-1 is able to form covalent complexes with plasmin. We hypothesized that plasmin-PN-1 complexes could be internalized via LRP-1 by vSMCs during the early stages of human atheroma. LRP-1 is also responsible for the capture of aggregated LDL in human atheroma. Plasmin activity and immunohistochemical analyses of early human atheroma showed that the plasminergic system is activated within the arterial wall, where intimal foam cells, including vSMCs and platelets, are the major sites of PN-1 accumulation. Both PN-1 and LRP-1 are overexpressed in early atheroma at both messenger and protein levels. Cell biology studies demonstrated an increased expression of PN-1 and tissue plasminogen activator by vSMCs in response to LDL. Plasmin-PN-1 complexes are internalized via LRP-1 in vSMCs, whereas plasmin alone is not. Tissue PN-1 interacts with plasmin in early human atheroma via two complementary mechanisms: plasmin inhibition and tissue uptake of plasmin-PN-1 complexes via LRP-1 in vSMCs. Despite this potential protective effect, plasminogen activation by vSMCs remains abnormally elevated in the intima in early stages of human atheroma.

6.
Prostaglandins Other Lipid Mediat ; 107: 48-55, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23850788

ABSTRACT

Prostacyclin (PGI2) and its mimetics (iloprost, treprostinil, beraprost and MRE-269) are potent vasodilators (via IP-receptor activation) and a major therapeutic intervention for pulmonary hypertension (PH). These PGI2 mimetics have anti-proliferative and potent vasodilator effects on pulmonary vessels. We compared the relaxant effects induced by these recognized IP-agonists in isolated human pulmonary arteries (HPA) and veins (HPV). In addition, using selective antagonists, the possible activation of other prostanoid relaxant receptors (DP, EP4) was investigated. Iloprost and treprostinil were the more potent relaxant agonists when both vessels were analyzed. HPA were significantly more sensitive to iloprost than to treprostinil, pEC50 values: 7.94±0.06 (n=23) and 6.73±0.08 (n=33), respectively. In contrast, in HPV these agonists were equipotent. The relaxations induced by treprostinil were completely or partially inhibited by IP-antagonists in HPA or HPV, respectively. The effects of the IP-agonists were not significantly modified by the EP4 antagonist. Finally, DP-antagonists inhibited the relaxations induced by treprostinil in HPV, suggesting that the DP-receptor plays a role in treprostinil-induced relaxation in the HPV. These data suggest that iloprost and treprostinil should be the most effective clinically available agonists to decrease pulmonary vascular resistance and to prevent oedema formation (by similar decrease in HPA and HPV resistance) in PH patients.


Subject(s)
Epoprostenol/analogs & derivatives , Epoprostenol/pharmacology , Iloprost/pharmacology , Vasodilator Agents/pharmacology , Acetates/pharmacology , Aged , Drug Evaluation, Preclinical , Female , Humans , In Vitro Techniques , Inhibitory Concentration 50 , Male , Middle Aged , Molecular Mimicry , Pulmonary Artery/drug effects , Pulmonary Artery/physiology , Pulmonary Veins/drug effects , Pulmonary Veins/physiology , Pyrazines/pharmacology , Receptors, Epoprostenol , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Prostaglandin/metabolism , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Vasodilation
7.
Article in English | MEDLINE | ID: mdl-23791663

ABSTRACT

Perivascular adipose tissue (PVAT) surrounds most vessels and has now been recognized as a regulator of vascular functions. This effect of PVAT has been mostly demonstrated in vessels obtained from rats and mice. Thus, the aim of this study was to investigate anti-contractile effect of PVAT surrounding human coronary bypass grafts such as saphenous vein (SV) and internal mammary artery (IMA). Moreover, we aimed to determine the involvement of prostanoids in the anticontractile effect of PVAT. Human SV and IMA preparations were set up in an organ bath. The presence of PVAT in SV and IMA preparations significantly attenuated the contractile response to noradrenaline (NA). Preincubation with indomethacin, a cyclooxygenase inhibitor, increased NA contraction in SV preparations with PVAT. This effect was not observed in IMA preparation with PVAT incubated with indomethacin. The lower measurements of prostaglandin E2 (PGE2) released from PVAT surrounding IMA versus SV supported these effects. In conclusion, our results show that PVAT of SV could attenuate NA-induced contraction by releasing both PGE2 and prostacyclin (PGI2). In contrast to SV, PVAT of IMA exerts its anti-contractile effect independently from prostanoids. These observations suggest that retaining PVAT in human SV and IMA preparations may have potential clinical implications to improve coronary bypass graft patency.


Subject(s)
Adipose Tissue, White/metabolism , Dinoprostone/physiology , Epoprostenol/physiology , Mammary Arteries/physiology , Saphenous Vein/physiology , Aged , Dinoprostone/pharmacology , Epoprostenol/pharmacology , Female , Humans , Indomethacin/pharmacology , Inhibitory Concentration 50 , Male , Mammary Arteries/drug effects , Middle Aged , Muscle Contraction , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Norepinephrine/pharmacology , Saphenous Vein/drug effects , Tissue Culture Techniques , Vasoconstriction , Vasoconstrictor Agents/pharmacology
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