Role of cytochrome P450-epoxygenase and soluble epoxide hydrolase in the regulation of vascular response

Abstract

The role of cytochrome P450-epoxygenase has been seen in cardiovascular physiology and pathophysiology. The aberration in CYP450-epoxygenase genes occur due to genetic polymorphisms, aging, or environmental factors, that increase susceptibility to cardiovascular diseases (CVDs). The actual role played by the CYP450-epoxygenases is the metabolism of arachidonic acid (AA) and linoleic acid (LA) into epoxyeicosatrienoic acids (EETs) and epoxyoctadecaenoic acid (EpOMEs) metabolites (oxylipins) and others, which is involved in vasodilation and myocardial-protection. But the genetic polymorphisms in CYP450-epoxygenases lose their beneficial cardiovascular effects of oxylipins, and the soluble epoxide hydrolase (sEH) antagonizes beneficial oxylipins into diols. Like sEH converts EETs into dihydroxyeicosatrienoic acid (DHETs), EpOMEs into dihydroxyoctadecaenoic acid (DiHOMEs), and reverses its beneficial effects, and the sEH gene (Ephx2) polymorphisms cause the enzyme to become overactive and convert epoxy-fatty acids into diols, making them vulnerable to CVDs, including hypertension. Other, enzymes like ω-hydroxylases (CYP450-4A11 & CYP450-4F2)-derived oxylipins from AA, ω-terminal-hydroxyeicosatetraenoic acids (19-, 20-HETE), lipoxygenase-derived oxylipins, mid-chain hydroxyeicosatetraenoic acids (5-, 11-, 12-, 15-HETEs), and the cyclooxygenase-derived prostanoids (prostaglandins: PGD₂, PGF_2α; thromboxane: Txs, oxylipins) are involved in vasoconstriction, hypertension, inflammation, and cardiac toxicity. Also, there are significant interactions were seen between adenosine receptors [adenosine A_2A receptor (A_2AAR) and adenosine A₁ receptor (A₁AR)] with CYP450-epoxygenases, ω-hydroxylases, sEH, and their derived oxylipins in the regulation of the cardiovascular response. Moreover, polymorphisms exist in CYP450-epoxygenases, ω-hydroxylases, sEH, and the adenosine receptor genes in populations associated with CVDs. This chapter will discuss the role of oxylipins' interactions with adenosine receptors in cardiovascular function/dysfunction in mice and humans.

Keywords: Adenosine A(1) receptor/adenosine A(2A) receptor; CYP450-epoxygenase/ω-hydroxylase; Cardiovascular response; Coronary reactive hyperemic response; Pro- and anti-inflammatory plasma/heart perfusate oxylipins; Soluble epoxide hydrolase.