Cytochrome P450-derived Epoxyeicosatrienoic Acid, the Regulation of Cardiovascular-related Diseases, and the Implication for Pulmonary Hypertension

Overview

Journal Cardiovasc Drugs Ther

Specialties Cardiology & Vascular Diseases
Pharmacology

Date 2024 Dec 9

PMID 39652233

Authors

Run Lan

Meng-Jie Zhang

Ke Liu

Fang-Fang Meng

Xiao-He Xu

Chen-Chen Wang

Meng-Qi Zhang

Yi Yan

Jie-Jian Kou

Lu-Ling Zhao

Yang-Yang He

Hong-Da Zhang

Affiliations

Soon will be listed here.

Abstract

Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid (AA) into biologically active epoxyeicosatrienoic acids (EETs), forming a pivotal metabolic pathway (AA-CYP-EETs-soluble epoxide hydrolase-dihydroxyeicosatrienoic acids) implicated in the progression of various disorders. Inflammation is a key contributor to the onset and progression of numerous systemic diseases, and EETs play a significant role in mitigating inflammation. Extensive research highlights the cardiovascular protective effects of EETs, which include vasodilation, anti-hypertensive, and anti-atherosclerotic properties. Interestingly, the relatively less-explored third metabolic pathway of AA exhibits both pro-proliferative and anti-apoptotic effects in endothelial cells and smooth muscle cells. Recent studies have shown elevated levels of EETs catalyzed by CYP epoxygenases in human tumors, promoting tumor progression and metastasis-phenomena closely related to the disease progression in pulmonary hypertension (PH). This review explores the current understanding of the regulatory functions of CYP-derived EETs in cardiovascular diseases and seeks to elucidate their potential implications in PH. Ultimately, understanding the multifaceted roles of EETs may help identify novel therapeutic targets for both cardiovascular diseases and PH.

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References

Galie N, Humbert M, Vachiery J, Gibbs S, Lang I, Torbicki A . 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS):.... Eur Heart J. 2015; 37(1):67-119. DOI: 10.1093/eurheartj/ehv317. View

McLaughlin V, Shah S, Souza R, Humbert M . Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015; 65(18):1976-97. DOI: 10.1016/j.jacc.2015.03.540. View

Humbert M, Lau E, Montani D, Jais X, Sitbon O, Simonneau G . Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2015; 130(24):2189-208. DOI: 10.1161/CIRCULATIONAHA.114.006974. View

Ryan J, Archer S . Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension. Circulation. 2015; 131(19):1691-702. PMC: 4429908. DOI: 10.1161/CIRCULATIONAHA.114.006979. View

Soon E, Holmes A, Treacy C, Doughty N, Southgate L, Machado R . Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010; 122(9):920-7. DOI: 10.1161/CIRCULATIONAHA.109.933762. View

Thenappan T, Ormiston M, Ryan J, Archer S . Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018; 360:j5492. PMC: 6889979. DOI: 10.1136/bmj.j5492. View

McReynolds C, Hammock B, Morisseau C . Regulatory lipid vicinal diols counteract the biological activity of epoxy fatty acids and can act as biomarkers and mechanisms for disease progression. Pharmacol Ther. 2023; 248:108454. PMC: 10529401. DOI: 10.1016/j.pharmthera.2023.108454. View

Atone J, Wagner K, Hashimoto K, Hammock B . Cytochrome P450 derived epoxidized fatty acids as a therapeutic tool against neuroinflammatory diseases. Prostaglandins Other Lipid Mediat. 2019; 147:106385. PMC: 7067627. DOI: 10.1016/j.prostaglandins.2019.106385. View

McGiff J . Cytochrome P-450 metabolism of arachidonic acid. Annu Rev Pharmacol Toxicol. 1991; 31:339-69. DOI: 10.1146/annurev.pa.31.040191.002011. View

10.

Jamieson K, Endo T, Darwesh A, Samokhvalov V, Seubert J . Cytochrome P450-derived eicosanoids and heart function. Pharmacol Ther. 2017; 179:47-83. DOI: 10.1016/j.pharmthera.2017.05.005. View

11.

Morisseau C, Inceoglu B, Schmelzer K, Tsai H, Jinks S, Hegedus C . Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids. J Lipid Res. 2010; 51(12):3481-90. PMC: 2975720. DOI: 10.1194/jlr.M006007. View

12.

Fang X, Weintraub N, McCaw R, Hu S, Harmon S, Rice J . Effect of soluble epoxide hydrolase inhibition on epoxyeicosatrienoic acid metabolism in human blood vessels. Am J Physiol Heart Circ Physiol. 2004; 287(6):H2412-20. DOI: 10.1152/ajpheart.00527.2004. View

13.

Panigrahy D, Greene E, Pozzi A, Wang D, Zeldin D . EET signaling in cancer. Cancer Metastasis Rev. 2011; 30(3-4):525-40. PMC: 3804913. DOI: 10.1007/s10555-011-9315-y. View

14.

Bieche I, Narjoz C, Asselah T, Vacher S, Marcellin P, Lidereau R . Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues. Pharmacogenet Genomics. 2007; 17(9):731-42. DOI: 10.1097/FPC.0b013e32810f2e58. View

15.

Konkel A, Schunck W . Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids. Biochim Biophys Acta. 2010; 1814(1):210-22. DOI: 10.1016/j.bbapap.2010.09.009. View

16.

McGiff J, Carroll M . Cytochrome P-450-related arachidonic acid metabolites. Am Rev Respir Dis. 1987; 136(2):488-91. DOI: 10.1164/ajrccm/136.2.488. View

17.

VanRollins M, Kaduce T, Knapp H, Spector A . 14,15-Epoxyeicosatrienoic acid metabolism in endothelial cells. J Lipid Res. 1993; 34(11):1931-42. View

18.

Fang X, VanRollins M, Kaduce T, Spector A . Epoxyeicosatrienoic acid metabolism in arterial smooth muscle cells. J Lipid Res. 1995; 36(6):1236-46. View

19.

Fang X, Kaduce T, Weintraub N, Spector A . Cytochrome P450 metabolites of arachidonic acid: rapid incorporation and hydration of 14,15-epoxyeicosatrienoic acid in arterial smooth muscle cells. Prostaglandins Leukot Essent Fatty Acids. 1998; 57(4-5):367-71. DOI: 10.1016/s0952-3278(97)90412-9. View

20.

VanRollins M, Kaduce T, Fang X, Knapp H, Spector A . Arachidonic acid diols produced by cytochrome P-450 monooxygenases are incorporated into phospholipids of vascular endothelial cells. J Biol Chem. 1996; 271(24):14001-9. DOI: 10.1074/jbc.271.24.14001. View