PMID- 35597366 OWN - NLM STAT- MEDLINE DCOM- 20221206 LR - 20221213 IS - 1879-016X (Electronic) IS - 0163-7258 (Linking) VI - 240 DP - 2022 Dec TI - Crosstalk between adenosine receptors and CYP450-derived oxylipins in the modulation of cardiovascular, including coronary reactive hyperemic response. PG - 108213 LID - S0163-7258(22)00107-3 [pii] LID - 10.1016/j.pharmthera.2022.108213 [doi] AB - Adenosine is a ubiquitous endogenous nucleoside or autacoid that affects the cardiovascular system through the activation of four G-protein coupled receptors: adenosine A(1) receptor (A(1)AR), adenosine A(2A) receptor (A(2A)AR), adenosine A(2B) receptor (A(2B)AR), and adenosine A(3) receptor (A(3)AR). With the rapid generation of this nucleoside from cellular metabolism and the widespread distribution of its four G-protein coupled receptors in almost all organs and tissues of the body, this autacoid induces multiple physiological as well as pathological effects, not only regulating the cardiovascular system but also the central nervous system, peripheral vascular system, and immune system. Mounting evidence shows the role of CYP450-enzymes in cardiovascular physiology and pathology, and the genetic polymorphisms in CYP450s can increase susceptibility to cardiovascular diseases (CVDs). One of the most important physiological roles of CYP450-epoxygenases (CYP450-2C & CYP2J2) is the metabolism of arachidonic acid (AA) and linoleic acid (LA) into epoxyeicosatrienoic acids (EETs) and epoxyoctadecaenoic acid (EpOMEs) which generally involve in vasodilation. Like an increase in coronary reactive hyperemia (CRH), an increase in anti-inflammation, and cardioprotective effects. Moreover, the genetic polymorphisms in CYP450-epoxygenases will change the beneficial cardiovascular effects of metabolites or oxylipins into detrimental effects. The soluble epoxide hydrolase (sEH) is another crucial enzyme ubiquitously expressed in all living organisms and almost all organs and tissues. However, in contrast to CYP450-epoxygenases, sEH converts EETs into dihydroxyeicosatrienoic acid (DHETs), EpOMEs into dihydroxyoctadecaenoic acid (DiHOMEs), and others and reverses the beneficial effects of epoxy-fatty acids leading to vasoconstriction, reducing CRH, increase in pro-inflammation, increase in pro-thrombotic and become less cardioprotective. Therefore, polymorphisms in the sEH gene (Ephx2) cause the enzyme to become overactive, making it more vulnerable to CVDs, including hypertension. Besides the sEH, omega-hydroxylases (CYP450-4A11 & CYP450-4F2) derived metabolites from AA, omega terminal-hydroxyeicosatetraenoic acids (19-, 20-HETE), lipoxygenase-derived mid-chain hydroxyeicosatetraenoic acids (5-, 11-, 12-, 15-HETEs), and the cyclooxygenase-derived prostanoids (prostaglandins: PGD(2), PGF(2alpha); thromboxane: Txs, oxylipins) are involved in vasoconstriction, hypertension, reduction in CRH, pro-inflammation and cardiac toxicity. Interestingly, the interactions of adenosine receptors (A(2A)AR, A(1)AR) with CYP450-epoxygenases, omega-hydroxylases, sEH, and their derived metabolites or oxygenated polyunsaturated fatty acids (PUFAs or oxylipins) is shown in the regulation of the cardiovascular functions. In addition, much evidence demonstrates polymorphisms in CYP450-epoxygenases, omega-hydroxylases, and sEH genes (Ephx2) and adenosine receptor genes (ADORA1 & ADORA2) in the human population with the susceptibility to CVDs, including hypertension. CVDs are the number one cause of death globally, coronary artery disease (CAD) was the leading cause of death in the US in 2019, and hypertension is one of the most potent causes of CVDs. This review summarizes the articles related to the crosstalk between adenosine receptors and CYP450-derived oxylipins in vascular, including the CRH response in regular salt-diet fed and high salt-diet fed mice with the correlation of heart perfusate/plasma oxylipins. By using A(2A)AR(-/-), A(1)AR(-/-), eNOS(-/-,) sEH(-/-) or Ephx2(-/-), vascular sEH-overexpressed (Tie2-sEH Tr), vascular CYP2J2-overexpressed (Tie2-CYP2J2 Tr), and wild-type (WT) mice. This review article also summarizes the role of pro-and anti-inflammatory oxylipins in cardiovascular function/dysfunction in mice and humans. Therefore, more studies are needed better to understand the crosstalk between the adenosine receptors and eicosanoids to develop diagnostic and therapeutic tools by using plasma oxylipins profiles in CVDs, including hypertensive cases in the future. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Nayeem, Mohammed A AU - Nayeem MA AD - Faculties of the Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA. Electronic address: mnayeem@hsc.wvu.edu. FAU - Hanif, Ahmad AU - Hanif A AD - Faculties of the Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA. FAU - Geldenhuys, Werner J AU - Geldenhuys WJ AD - Faculties of the Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA. FAU - Agba, Stephanie AU - Agba S AD - Graduate student, Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20220518 PL - England TA - Pharmacol Ther JT - Pharmacology & therapeutics JID - 7905840 RN - 0 (Oxylipins) RN - EC 3.3.2.- (Epoxide Hydrolases) RN - 0 (Nucleosides) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - 0 (Hydroxyeicosatetraenoic Acids) RN - 27YG812J1I (Arachidonic Acid) RN - 0 (Receptors, Purinergic P1) RN - K72T3FS567 (Adenosine) SB - IM MH - Humans MH - Mice MH - Animals MH - *Hyperemia/metabolism MH - Oxylipins/metabolism MH - Epoxide Hydrolases/metabolism MH - Nucleosides MH - Cytochrome P-450 Enzyme System/genetics/metabolism MH - Hydroxyeicosatetraenoic Acids MH - Heart MH - Arachidonic Acid/metabolism MH - *Cardiovascular Diseases/genetics MH - Receptors, Purinergic P1/genetics MH - *Hypertension MH - Adenosine OTO - NOTNLM OT - Adenosine receptors OT - CYP450-enzymes OT - Coronary reactive hyperemia OT - Plasma/heart perfusate oxylipins OT - Soluble epoxide hydrolase OT - Vascular response COIS- Conflict of Interest The authors (Mohammed Nayeem, Ahmad Hanif, Werner Geldenhuys, and Stephanie Agba) have no conflict of interests to declare. EDAT- 2022/05/22 06:00 MHDA- 2022/12/07 06:00 CRDT- 2022/05/21 19:24 PHST- 2022/01/31 00:00 [received] PHST- 2022/05/11 00:00 [revised] PHST- 2022/05/12 00:00 [accepted] PHST- 2022/05/22 06:00 [pubmed] PHST- 2022/12/07 06:00 [medline] PHST- 2022/05/21 19:24 [entrez] AID - S0163-7258(22)00107-3 [pii] AID - 10.1016/j.pharmthera.2022.108213 [doi] PST - ppublish SO - Pharmacol Ther. 2022 Dec;240:108213. doi: 10.1016/j.pharmthera.2022.108213. Epub 2022 May 18.