The cytochrome P450 (CYP) epoxygenase enzymes CYP2J and CYP2C catalyze the epoxidation of arachidonic acid to epoxyeicosatrienoic acids (EETs), which are rapidly hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). It is well-established that CYP epoxygenase-derived EETs possess potent vasodilatory effects; however, the cellular effects of EETs and their regulation of various inflammatory processes have become increasingly appreciated in recent years, suggesting that the role of this pathway in the cardiovascular system extends beyond the maintenance of vascular tone. In particular, CYP epoxygenase-derived EETs inhibit endothelial activation and leukocyte adhesion via attenuation of nuclear factor-kappaB activation, inhibit hemostasis, protect against myocardial ischemia-reperfusion injury, and promote endothelial cell survival via modulation of multiple cell signaling pathways. Thus, the CYP epoxygenase pathway is an emerging target for pharmacological manipulation to enhance the cardiovascular protective effects of EETs. This review will focus on the role of the CYP epoxygenase pathway in the regulation of cardiovascular inflammation, and 1) describe the functional impact of CYP epoxygenase-derived EET biosynthesis and sEH-mediated EET hydrolysis on key inflammatory process in the cardiovascular system, 2) discuss the potential relevance of this pathway to pathogenesis and treatment of cardiovascular disease, and 3) identify areas for future research.

Cytochrome P-450 (CYP)-derived epoxyeicosatrienoic acids (EETs) possess potent anti-inflammatory effects in vitro. However, the effect of increased CYP-mediated EET biosynthesis and decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on vascular inflammation in vivo has not been rigorously investigated. Consequently, we characterized acute vascular inflammatory responses to endotoxin in transgenic mice with endothelial expression of the human CYP2J2 and CYP2C8 epoxygenases and mice with targeted disruption of Ephx2. Compared to wild-type controls, CYP2J2 transgenic, CYP2C8 transgenic, and Ephx2(-/-) mice each exhibited a significant attenuation of endotoxin-induced activation of nuclear factor (NF)-κB signaling, cellular adhesion molecule, chemokine and cytokine expression, and neutrophil infiltration in lung in vivo. Furthermore, attenuation of endotoxin-induced NF-κB activation and cellular adhesion molecule and chemokine expression was observed in primary pulmonary endothelial cells isolated from CYP2J2 and CYP2C8 transgenic mice. This attenuation was inhibited by a putative EET receptor antagonist and CYP epoxygenase inhibitor, directly implicating CYP epoxygenase-derived EETs with the observed anti-inflammatory phenotype. Collectively, these data demonstrate that potentiation of the CYP epoxygenase pathway by either increased endothelial EET biosynthesis or globally decreased EET hydrolysis attenuates NF-κB-dependent vascular inflammatory responses in vivo and may serve as a viable anti-inflammatory therapeutic strategy.

ABSTRACT:Cytochrome P450 (P450)-mediated metabolism of arachidonic acid regulates inflammation in hepatic and extrahepatic tissue. CYP2C/ CYP2J-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET؉DHET) elicit anti-inflammatory effects, whereas CYP4A/ CYP4F-derived 20-hydroxyeicosatetraenoic acid (20-HETE) is proinflammatory. Because the impact of inflammation on P450-mediated formation of endogenous eicosanoids is unclear, we evaluated P450 mRNA levels and P450 epoxygenase (EET؉DHET) and -hydroxylase (20-HETE) metabolic activity in liver, kidney, lung, and heart in mice 3, 6, 24, and 48 h after intraperitoneal lipopolysaccharide (LPS) (1 mg/kg) or saline administration. Hepatic Cyp2c29, Cyp2c44, and Cyp2j5 mRNA levels and EET؉DHET formation were significantly lower 24 and 48 h after LPS administration. Hepatic Cyp4a12a, Cyp4a12b, and Cyp4f13 mRNA levels and 20-HETE formation were also significantly lower at 24 h, but recovered to baseline at 48 h, resulting in a significantly higher 20-HETE/EET؉DHET formation rate ratio compared with that for saline-treated mice. Renal P450 mRNA levels and P450-mediated eicosanoid metabolism were similarly suppressed 24 h after LPS treatment. Pulmonary EET؉DHET formation was lower at all time points after LPS administration, whereas 20-HETE formation was suppressed in a time-dependent manner, with the lowest formation rate observed at 24 h. No differences in EET؉DHET or 20-HETE formation were observed in heart. Collectively, these data demonstrate that acute activation of the innate immune response alters P450 expression and eicosanoid metabolism in mice in an isoform-, tissue-, and time-dependent manner. Further study is necessary to determine whether therapeutic restoration of the functional balance between the P450 epoxygenase and -hydroxylase pathways is an effective anti-inflammatory strategy.

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