Inside epoxyeicosatrienoic acids and cardiovascular disease

Tacconelli, Stefania; Patrignani, Paola

doi:10.3389/fphar.2014.00239

Cited by 47 publications

(26 citation statements)

References 53 publications

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“…In arachidonate cascade, the P450 epoxygenase is unique in regio- and stereochemical selectivity to biosynthesize EET mediators. EETs are known to reduce infarct size, preserve LV function and limit cardiac hypertrophy [35, 36]. CYP2J subfamilies of CYP are abundantly expressed in the cardiovascular system and metabolize AA to produce four biologically active EETs: 5,6 (cypoxins; CExn1)-, 8,9 (CExn2)-, 11,12 (CExn3)-, and 14,15 (CExn4)-EETs [37].…”

Section: Discussionmentioning

confidence: 99%

Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

Kain

Ingle

Kabarowski

et al. 2018

Journal of Molecular and Cellular Cardiology

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12/15 lipoxygenase (LOX) directs inflammation and lipid remodeling. However, the role of 12/15LOX in post-myocardial infarction (MI) left ventricular remodeling is unclear. To determine the role of 12/15LOX, 8-12 week-old C57BL/6J wild-type (WT; n=93) and 12/15LOX−/− (n=97) mice were subjected to permanent coronary artery ligation and monitored at day (d)1 and d5 post-operatively. Post-MI d28 survival was measured in male and female mice. No-MI surgery mice were maintained as d0 naïve controls. 12/15LOX-/- mice exhibited higher survival rates with lower cardiac rupture and improved LV function as compared with WT post-MI. Compared to WT, neutrophils and macrophages in 12/15LOX-/- mice were polarized towards N2 and M2 phenotypes, respectively, with increased of expression mrc-1, ym-1, and arg-1 post-MI. 12/15LOX-/- mice exhibited lower levels of pro-inflammatory 12-(S)-hydroperoxyeicosatetraenoic acid (12(S)-HETE) and higher CYP2J-derived epoxyeicosatrienoic acids (EETs) levels. CYP2J-derived 5,6-, 8,9-, 11,12-, and 14,15-EETs activated macrophage-specific hemeoxygenase (HO)-1 marked with increases in F4/80+/Ly6Clow and F4/80+/CD206high cells at d5 post-MI in 12/15LOX-/- mice. In contrast, inhibition of HO-1 led to total mortality in 12/15LOX-/- mice by post-MI d5. 12/15LOX-/- mice exhibited reduced collagen density and lower α-smooth muscle actin (SMA) expression at d5 post-MI, indicating delayed or limited fibroblast-to-myofibroblast differentiation. In conclusion, genetic deletion of 12/15LOX reduces 12(S)-HETE and activates CYP2J-derived EETs to promote effective resolution of inflammation post-MI leading to reduced cardiac rupture, improved LV function, and better survival.

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Section: Discussionmentioning

confidence: 99%

Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

Kain

Ingle

Kabarowski

et al. 2018

Journal of Molecular and Cellular Cardiology

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“…Similar to CYP4 enzymes, expression of CYP2J2 is upregulated in tumor cells of human origin compared to adjacent normal cells corresponding to an increase in EET formation (Wang & Dubois, 2010). Interestingly, during cancer progression, EETs generated by CYP2C and CYP2J appear to play rather similar roles to 20-HETE, in that they also stimulate tumor cell proliferation, inhibition of apoptosis, angiogenesis, and metastases in a variety of mouse tumors (Tacconelli & Patrignani, 2014). EETs also appear to participate in signaling pathways that mirror several of those invoked for 20-HETE's protumorigenic effects including VEGF, MAPK, and PI3K/Akt.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer

Johnson

Edson

Totah

et al. 2015

Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer

115

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Cytochrome P450-dependent ω-hydroxylation is a prototypic metabolic reaction of CYP4 family members that is important for the elimination and bioactivation of not only therapeutic drugs, but also endogenous compounds, principally fatty acids. Eicosanoids, derived from arachidonic acid, are key substrates in the latter category. Human CYP4 enzymes, mainly CYP4A11, CYP4F2, and CYP4F3B, hydroxylate arachidonic acid at the omega position to form 20-HETE, which has important effects in tumor progression and on angiogenesis and blood pressure regulation in the vasculature and kidney. CYP4F3A in myeloid tissue catalyzes the ω-hydroxylation of leukotriene B4 to 20-hydroxy leukotriene B4, an inactivation process that is critical for the regulation of the inflammatory response. Here, we review the enzymology, tissue distribution, and substrate selectivity of human CYP4 ω-hydroxylases and their roles as catalysts for the formation and termination of the biological effects of key eicosanoid metabolites in inflammation and cancer progression.

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“…To this end, soluble epoxide hydrolase inhibitors, being considered for the treatment of hypertension, increase epoxyeicosatrienoic acids (EET) in human coronary arterioles and can augment vasodilation via these vasoprotective compounds 55 . Potential benefits of enhancing EET release include reduced apoptosis 56 and inhibition vascular inflammation, thrombosis, and proliferation 57 .…”

Section: The Microcirculation As a Window Into Conduit Artery Diseasementioning

confidence: 99%

The Human Microcirculation

Gutterman

Chabowski

Kadlec

et al. 2016

Circulation Research

230

141

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The microcirculation is responsible for orchestrating adjustments in vascular tone to match local tissue perfusion with oxygen demand. Beyond this metabolic dilation, the microvasculature plays a critical role in modulating vascular tone by endothelial release of an unusually diverse family of compounds including nitric oxide, other reactive oxygen species, and arachidonic acid metabolites. Animal models have provided excellent insight into mechanisms of vasoregulation in health and disease. However there are unique aspects of the human microcirculation that serve as the focus of this review. The concept is put forth that vasculo-parenchymal communication is multimodal, with vascular release of nitric oxide eliciting dilation and preserving normal parenchymal function by inhibiting inflammation and proliferation. Likewise, in disease or stress, endothelial release of ROS both mediates dilation and parenchymal inflammation leading to cellular dysfunction, thrombosis, and fibrosis. Some pathways responsible for this stress-induced shift in mediator of vasodilation are proposed. This paradigm may help explain why microvascular dysfunction is such a powerful predictor of cardiovascular events, and help identify new approaches to treatment and prevention.

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Inside epoxyeicosatrienoic acids and cardiovascular disease

Cited by 47 publications

References 53 publications

Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer

The Human Microcirculation

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