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Wang J, Hu S, Xu Y, Wang T. Omega-6 polyunsaturated fatty acids and their metabolites: a potential targeted therapy for pulmonary hypertension. Respir Res 2025; 26:102. [PMID: 40089708 PMCID: PMC11909876 DOI: 10.1186/s12931-025-03172-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/26/2025] [Indexed: 03/17/2025] Open
Abstract
Pulmonary hypertension (PH) is a progressive and life-threatening cardiopulmonary disease that is not uncommon. The modulation of the pulmonary artery (PA) involves various fatty acids, including omega-6 polyunsaturated fatty acids (ω-6 PUFAs) and ω-6 PUFAs-derived oxylipins. These lipid mediators are produced through cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP450), and non-enzymatic pathways. They play a crucial role in the occurrence and development of PH by regulating the function and phenotype of pulmonary artery endothelial cells (PAECs), pulmonary artery smooth muscle cells (PASMCs), pulmonary fibroblasts, alveolar macrophages, and inflammatory cells. The alterations in ω-6 PUFAs and oxylipins are pivotal in causing vasoconstriction, pulmonary remodeling, and ultimately leading to right heart failure in PH. Despite the limited understanding of the PH pathophysiology, there is potential for novel interventions through dietary and pharmacological approaches targeting ω-6 PUFAs and oxylipins. The aim of this review is to summarize the significant advances in clinical and basic research on omega-6 PUFAs and oxylipins in pulmonary vascular disease, particularly PH, and to propose a potential targeted therapeutic modality against omega-6 PUFAs.
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Affiliation(s)
- Jiayao Wang
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
- The Center for Biomedical Research, Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, National Health Committee (NHC), Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shunlian Hu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
- The Center for Biomedical Research, Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, National Health Committee (NHC), Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yahan Xu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
- The Center for Biomedical Research, Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, National Health Committee (NHC), Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Tao Wang
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
- The Center for Biomedical Research, Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, National Health Committee (NHC), Huazhong University of Science and Technology, Wuhan, People's Republic of China.
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Wong SL, Wong WT, Tian XY, Lau CW, Huang Y. Prostaglandins in action indispensable roles of cyclooxygenase-1 and -2 in endothelium-dependent contractions. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2010; 60:61-83. [PMID: 21081215 DOI: 10.1016/b978-0-12-385061-4.00003-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Endothelium regulates local vascular tone by means of releasing relaxing and contracting factors, of which the latter have been found to be elevated in vascular pathogenesis of hypertension, diabetes, hypercholesterolemia, and aging. Endothelium-derived contracting factors (EDCFs) are mainly metabolites of arachidonic acid generated by cyclooxygenase (COX), as vasodilatations in patients with hypertension, metabolic diseases, or advancing age are improved by acute treatment with COX inhibitor indomethacin. COX is presented in two isoforms, COX-1 and COX-2, with the former regarded as constitutive and the latter mainly expressed upon induction. Experiments with animal models of vascular dysfunctions, however, reveal that both isoforms have similar capacity to participate in endothelium-dependent contractions, with augmented expression and activity. COX-derived prostaglandin (PG) H(2), PGF(2α), PGE(2), prostacyclin (PGI(2)), and thromboxane A(2) (TxA(2)) are the proposed EDCFs that mediate endothelium-dependent contractions via the activation of thromboxane-prostanoid (TP) receptor in various vascular beds from different species. Although COX inhibition seems to be a possible strategy in combating COX-associated vascular complications, the incidence of adverse cardiovascular effects of Vioxx has greatly antagonized this concept. Further review of COX inhibitors is required, especially toward the selectivity of coxibs and whether it directly inhibits prostacyclin synthase activity. Meanwhile, TP receptor antagonism may emerge as a therapeutic alternative to reverse prostanoid-mediated vascular dysregulations.
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Affiliation(s)
- Siu Ling Wong
- Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
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Tiwari R, Singh V, Barthwal M. Macrophages: An elusive yet emerging therapeutic target of atherosclerosis. Med Res Rev 2008; 28:483-544. [DOI: 10.1002/med.20118] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Stapleton PA, Goodwill AG, James ME, Frisbee JC. Altered mechanisms of endothelium-dependent dilation in skeletal muscle arterioles with genetic hypercholesterolemia. Am J Physiol Regul Integr Comp Physiol 2007; 293:R1110-9. [PMID: 17626122 DOI: 10.1152/ajpregu.00410.2007] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
With most cardiovascular disease risk factors, endothelium-dependent dilation of skeletal muscle resistance arterioles is compromised, although with hypercholesterolemia, impairments to reactivity are not consistently observed. Using apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) gene deletion male mouse models of hypercholesterolemia at 20 wk of age, we tested the hypothesis that arteriolar dilation would be maintained due to an increased stimulus-induced production of dilator metabolites via cyclooxygenase and cytochrome P-450 epoxygenase pathways. Arterioles from both strains demonstrated mild reductions in dilation to hypoxia and acetylcholine versus responses in C57/Bl/6J (C57) controls. However, although inhibition of nitric oxide synthase (NOS) attenuated dilation in arterioles from C57 controls, this effect was absent in ApoE or LDLR strains. In contrast, cyclooxygenase-dependent portions of dilator reactivity were maintained across the three strains. Notably, although combined NOS and cyclooxygenase inhibition abolished arteriolar responses to hypoxia and acetylcholine in C57 controls, significant reactivity remained in ApoE and LDLR strains. Whereas inhibition of cytochrome P-450 omega-hydroxylase and epoxygenases had no effect on this residual reactivity in ApoE and LDLR strains, inhibition of 12/15-lipoxygenase with nordihydroguaiaretic acid abolished the residual reactivity. With both hypoxic and methacholine challenges, arteries from ApoE and LDLR strains demonstrated an increased production of both 12(S)- and 15(S)-hydroxyeicosatetraenoic acid, end products of arachidonic acid metabolism via 12/15-lipoxygenase, a response that was not present in C57 controls. These results suggest that with development of hypercholesterolemia, mechanisms contributing to dilator reactivity in skeletal muscle arterioles are modified such that net reactivity to endothelium-dependent stimuli is largely intact.
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Affiliation(s)
- Phoebe A Stapleton
- Center for Interdisciplinary Research in Cardiovascular Science, Department of Physiology and Pharmacology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV 26505, USA
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Abstract
Treatment of thrombotic diseases implicates the use of anti-platelet agents, anti-coagulants and pro-fibrinolytic substances. Amongst the anti-platelet drugs, aspirin occupies a unique position. As soon as it became evident that the major action of aspirin is indirect blockade, through inhibition of cyclooxygenase (COX), of the production of thromboxane A2 (TXA2), a powerful vasoconstrictor and platelet activator, research for new anti-thrombotics that interact more specifically with the production and/or the action of TXA2 was started. Terutroban (S 18886) is a selective antagonist of TP receptors, the receptors for TXA2, that are present on platelets and on vascular smooth muscle cells, but also on endothelial cells. The role played by the platelet and smooth muscle cell TP receptors in thrombotic disease is well known, and preclinical and clinical studies with terutroban have illustrated the powerful antithrombotic effects of this agent. The implication of endothelial TP receptors in the development of atherosclerotic disease has only been examined during the past five years and studies with terutroban have been crucial for understanding the role of these endothelial receptors in cardiovascular physiopathology. The goal of the present review is to discuss the arguments in favour of the hypothesis suggesting that activation of endothelial TP receptors, by causing expression of adhesion molecules, favours adhesion and infiltration of monocytes/macrophages in the arterial wall, thereby stimulating the development of atherosclerosis. The review will also highlight the important contribution of the studies performed with terutroban in this research area. The triple activity (anti-thrombotic, anti-vasoconstrictor, anti-atherosclerotic) observed with terutroban in preclinical studies, stressed by the first results in clinical development, places terutroban as an innovative drug with a unique potential for treatment of cardiovascular disorders.
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Affiliation(s)
- Tony J Verbeuren
- Division d'Angiologie, Institut de Recherche Servier, 11, rue des Moulineaux, 92150 Suresnes, France.
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Dogné JM, Hanson J, Pratico D. Thromboxane, prostacyclin and isoprostanes: therapeutic targets in atherogenesis. Trends Pharmacol Sci 2005; 26:639-44. [PMID: 16243403 DOI: 10.1016/j.tips.2005.10.001] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2005] [Revised: 08/22/2005] [Accepted: 10/06/2005] [Indexed: 01/18/2023]
Abstract
Atherosclerosis is a chronic disease of the vasculature that is influenced by multiple factors that involve a complex interplay between some components of the blood and the arterial wall. Inflammation and oxidative stress have key roles in atherogenesis. The production of F2-isoprostanes (F2-IPs), thromboxane A2 (TxA2) and prostacyclin (PGI2) increases in atherosclerosis, and recent studies show that pharmacological modulation of their biosynthesis and biological activities are important therapeutic targets for managing atherosclerosis. In this review, we highlight recent breakthroughs in the roles of F2-IPs, TxA2 and PGI2 in atherogenesis, and identify pertinent therapeutic targets.
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Affiliation(s)
- Jean-Michel Dogné
- Department of Pharmacy, University of Namur, rue de Bruxelles 61, B-5000 Namur, Belgium.
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Abstract
This review focuses on the role of monocytes in the early phase of atherogenesis, before foam cell formation. An emerging consensus underscores the importance of the cellular inflammatory system in atherogenesis. Initiation of the process apparently hinges on accumulating low-density lipoproteins (LDL) undergoing oxidation and glycation, providing stimuli for the release of monocyte attracting chemokines and for the upregulation of endothelial adhesive molecules. These conditions favor monocyte transmigration to the intima, where chemically modified, aggregated, or proteoglycan- or antibody-complexed LDL may be endocytotically internalized via scavenger receptors present on the emergent macrophage surface. The differentiating monocytes in concert with T lymphocytes exert a modulating effect on lipoproteins. These events propagate a series of reactions entailing generation of lipid peroxides and expression of chemokines, adhesion molecules, cytokines, and growth factors, thereby sustaining an ongoing inflammatory process leading ultimately to lesion formation. New data emerging from studies using transgenic animals, notably mice, have provided novel insights into many of the cellular interactions and signaling mechanisms involving monocytes/macrophages in the atherogenic processes. A number of these studies, focusing on mechanisms for monocyte activation and the roles of adhesive molecules, chemokines, cytokines and growth factors, are addressed in this review.
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Affiliation(s)
- Bjarne Osterud
- Department of Biochemistry, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, Tromsø, Norway.
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Wang XJ, Wei JG, Wang CM, Wang YC, Wu QZ, Xu JK, Yang XX. Effect of cholesterol liposomes on calcium mobilization in muscle cells from the rabbit sphincter of Oddi. World J Gastroenterol 2002; 8:144-9. [PMID: 11833091 PMCID: PMC4656607 DOI: 10.3748/wjg.v8.i1.144] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the influence of cholesterol liposome on the Ca2+ mobilization of cultured muscle cells in rabbit sphincter of Oddi’s.
METHODS: New Zealand rabbit was sacrificed and the sphincter of Oddi (SO) segement was obtained aseptically. The SO segment was cut into pieces and cultured in DMEM solution. Then the smooth muscle cells were subcultured, and the 4th-7th passage cells were used for further investigation. The intracellular Ca2+ increase was measured under confocal microscope after the addition of 20 mmol·L-1 KCl, 10-7 mol·L-1 acetylcholine and 10-7 mol·L-1 cholecystokinin, and different antagonists were added to analyze the Ca2+ mobilization pathway. After the cells were incubated with 1 g·L-1 cholesterol liposome (CL)(molar ratio was-2:1), the intracellular Ca2+ increase was measured again to determine the effect of CL on cellular Ca2+ mobilization.
RESULTS: The resting cellular calcium concentration of cultured SO cell was 108 nmol·L-1± 21 nmol·L-1. The intracellular Ca2+ increases induced by 20 mmol·L-1 KCl, 10-7 mol·L-1 ACh and 10-7 mol·L-1 CCK were 183% ± 56%, 161% ± 52% and 130% ± 43%, respectively. When the extracellular Ca2+ was eliminated by 2 mmol·L-1 EGTA and 5 μmol·L-1 verapamil, the intracellular Ca2+ increases induced by KCl, ACh and CCK were 20% ± 14%, 82% ± 21% and 104% ± 23%, respectively. After the preincubation with heparin, the Ca2+ increases were 62% ± 23% and 23% ± 19% induced by ACh and CCK, as for preincubation with procaine they were 72% ± 28% and 85% ± 37% induced by ACh and CCK, respectively. Pretreatment with CL for 18 h, the resting cellular Ca2+ concentration elevated to 152 nmol·L-1± 26 nmol·L-1, however, the cellular Ca2+ increase percentages in response to these agonists were 67% ± 32%, 56% ± 33% and 34% ± 15%.
CONCLUSION: KCl elicite the SO cellular Ca2+ increase depends on influx of extracellular Ca2+, ACh evoked the SO celllular Ca2+ increase is through the mobilization of intracellular Ca2+ pool and influx of extracellular Ca2+ as well, CCK excites the SO cells mainly through mobilization of intracellular IP3-sensitive Ca2+ store. After the incorporation with cholesterol liposome, KCl,ACh and CCK induced cellular Ca2+ increase percentages decreased.
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Affiliation(s)
- Xin-Jiang Wang
- Department of Radiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, Shaanxi Province,China.
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Cayatte AJ, Du Y, Oliver-Krasinski J, Lavielle G, Verbeuren TJ, Cohen RA. The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20:1724-8. [PMID: 10894809 DOI: 10.1161/01.atv.20.7.1724] [Citation(s) in RCA: 167] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A(2). The actions of TxA(2) as well as of other arachidonic acid products, such as prostaglandin (PG) H(2), PGF(2alpha), hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this study was to determine the role of platelet-derived TxA(2) in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist S18886. The effect of 11 weeks of treatment with aspirin (30 mg. kg(-1). d(-1)) or S18886 (5 mg. kg(-1). d(-1)) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA(2) metabolite TxB(2) was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB(2) levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA(2). S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA(2) synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels. The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA(2), perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA(2).
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Affiliation(s)
- A J Cayatte
- Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, MA 02118, USA
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