Cytochrome P450-derived Eicosanoids, Inflammation, and Atherosclerotic Cardiovascular Disease

Inflammation contributes to the pathogenesis of atherosclerosis from the initiation of plaque formation to progression to acute coronary syndrome clinical events. Due to the divergent effects of cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) in the regulation of vascular tone and inflammation, alterations in the functional balance between the CYP epoxygenase and ω-hydroxylase pathways may contribute to the pathophysiology of cardiovascular disease. The objectives of the work described in this doctoral dissertation were to characterize the effect of inflammation, metabolic dysfunction, and cardiovascular disease on the functional balance between the CYP epoxygenase and ω-hydroxylase pathways, and explore the potential of modulating CYP-mediated eicosanoid metabolism as an anti-inflammatory therapeutic strategy for atherosclerotic cardiovascular disease. Acute activation of the innate immune response altered CYP-mediated eicosanoid metabolism in a tissue- and time-dependent manner. High fat diet feeding shifted the functional balance between the pathways in favor of the CYP ω-hydroxylase pathway, suggesting that dysregulation of CYP-mediated eicosanoid metabolism contributes to the pathophysiologic consequences of the metabolic syndrome. Enalapril treatment restored the functional balance between the pathways, implicating the renin-angiotensin system in mediating high fat diet-induced alterations in CYP-mediated eicosanoid metabolism. Although 20-HETE does not contribute to the acute inflammatory response to lipopolysaccharide, inhibition of the CYP ω-hydroxylase pathway may have therapeutic utility for the treatment of chronic vascular inflammation. CYP epoxygenase and ω-hydroxylase pathway function differed between healthy volunteers and patients with established atherosclerosis, and several clinical factors were associated with plasma levels of CYP-derived eicosanoids. Functional genetic variation in the CYP epoxygenase and ω-hydroxylase pathways was associated with survival in patients following an acute coronary syndrome, suggesting that therapies that specifically modulate CYP-mediated eicosanoid metabolism may represent a novel treatment strategy for atherosclerotic cardiovascular disease

Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation

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

Dual modulation of cyclooxygenase and CYP epoxygenase metabolism and acute vascular inflammation in mice

Cyclooxygenase (COX)-derived prostaglandins and cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids are important regulators of inflammation; however, functional interactions between these pathways in the regulation of vascular inflammation in vivo have not been studied. We investigated the relative and additive effects of endothelial CYP2J2 overexpression (Tie2-CYP2J2-Tr), global sEH disruption (Ephx2−/−), and pharmacologic COX inhibition with indomethacin on the acute vascular inflammatory response to endotoxin in mice. Compared to vehicle-treated wild-type C57BL/6 controls, induction of myeloperoxidase (MPO) activity in lung and liver was similarly attenuated in Tie2-CYP2J2-Tr mice, Ephx2−/− mice and wild-type mice treated with moderate dose indomethacin. Dual modulation of both pathways, however, did not produce an additive anti-inflammatory effect. These findings demonstrate that both COX and CYP epoxygenase-mediated eicosanoid metabolism are important regulators of the acute vascular inflammatory response in vivo, and suggest that the anti-inflammatory effects of modulating each pathway may be mediated, at least in part, by overlapping mechanisms

Evaluation of cytochrome P450-derived eicosanoids in humans with stable atherosclerotic cardiovascular disease

Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronary artery disease (CAD). However, predictors of inter-individual variation in CYP-derived eicosanoid metabolites in CAD patients have not been evaluated to date. Therefore, the primary objective was to identify clinical factors that influence CYP epoxygenase, soluble epoxide hydrolase (sEH), and CYP ω-hydroxylase metabolism in patients with established CAD

Cytochrome P450-derived eicosanoids and vascular dysfunction in coronary artery disease patients

Accumulating preclinical and epidemiologic evidence has emerged to suggest that modulation of cytochrome P450 (CYP)-mediated eicosanoid metabolism may be a viable vascular protective therapeutic strategy for the secondary prevention of coronary artery disease (CAD). The functional relationship between CYP-derived eicosanoid metabolite levels and vascular dysfunction in humans with established CAD, however, has not been evaluated. Therefore, we characterized the relationship between inter-individual variation in soluble epoxide hydrolase (sEH) and CYP ω-hydroxylase metabolism and established vascular function phenotypes predictive of prognosis in a cohort of patients with atherosclerotic cardiovascular disease

Cytochrome P450-derived eicosanoids, inflammation, and atherosclerotic cardiovascular disease

Inflammation contributes to the pathogenesis of atherosclerosis from the initiation of plaque formation to progression to acute coronary syndrome clinical events. Due to the divergent effects of cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) in the regulation of vascular tone and inflammation, alterations in the functional balance between the CYP epoxygenase and ω-hydroxylase pathways may contribute to the pathophysiology of cardiovascular disease. The objectives of the work described in this doctoral dissertation were to characterize the effect of inflammation, metabolic dysfunction, and cardiovascular disease on the functional balance between the CYP epoxygenase and ω-hydroxylase pathways, and explore the potential of modulating CYP-mediated eicosanoid metabolism as an anti-inflammatory therapeutic strategy for atherosclerotic cardiovascular disease. Acute activation of the innate immune response altered CYP-mediated eicosanoid metabolism in a tissue- and time-dependent manner. High fat diet feeding shifted the functional balance between the pathways in favor of the CYP ω-hydroxylase pathway, suggesting that dysregulation of CYP-mediated eicosanoid metabolism contributes to the pathophysiologic consequences of the metabolic syndrome. Enalapril treatment restored the functional balance between the pathways, implicating the renin-angiotensin system in mediating high fat diet-induced alterations in CYP-mediated eicosanoid metabolism. Although 20-HETE does not contribute to the acute inflammatory response to lipopolysaccharide, inhibition of the CYP ω-hydroxylase pathway may have therapeutic utility for the treatment of chronic vascular inflammation. CYP epoxygenase and ω-hydroxylase pathway function differed between healthy volunteers and patients with established atherosclerosis, and several clinical factors were associated with plasma levels of CYP-derived eicosanoids. Functional genetic variation in the CYP epoxygenase and ω-hydroxylase pathways was associated with survival in patients following an acute coronary syndrome, suggesting that therapies that specifically modulate CYP-mediated eicosanoid metabolism may represent a novel treatment strategy for atherosclerotic cardiovascular disease

Weight-adjusted aspirin for cardiovascular prevention

Theken KN, Grosser T. Weight-adjusted aspirin for cardiovascular prevention. The Lancet. 2018;392(10145):361-362

Association between the EPHX2 p.Lys55Arg polymorphism and prognosis following an acute coronary syndrome

Inhibition of soluble epoxide hydrolase (sEH, EPHX2) elicits potent cardiovascular protective effects in preclinical models of ischemic cardiovascular disease (CVD), and genetic polymorphisms in EPHX2 have been associated with developing ischemic CVD in humans. However, it remains unknown whether EPHX2 variants are associated with prognosis following an ischemic CVD event. We evaluated the association between EPHX2 p.Lys55Arg and p.Arg287Gln genotype with survival in 667 acute coronary syndrome (ACS) patients. No association with p.Arg287Gln genotype was observed (P = 0.598). Caucasian EPHX2 Arg55 carriers (Lys/Arg or Arg/Arg) had a significantly higher risk of 5-year mortality (adjusted hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.01-2.55, P = 0.045). In an independent population of 2712 ACS patients, this association was not replicated (adjusted HR 0.92, 95% CI 0.70-1.21, P = 0.559). In a secondary analysis, Caucasian homozygous Arg55 allele carriers (Arg/Arg) appeared to exhibit a higher risk of cardiovascular mortality (adjusted HR 2.60, 95% CI 1.09-6.17). These results demonstrate that EPHX2 p.Lys55Arg and p.Arg287Gln polymorphisms do not significantly modify survival after an ACS event. Investigation of other sEH metabolism biomarkers in ischemic CVD appears warranted

Editorial: NSAIDs Pharmacogenomics

Agúndez JAG, Formea C, Gaedigk A, et al. Editorial: NSAIDs Pharmacogenomics. Frontiers in Pharmacology. 2021;12