Arachidonic acid (AA) metabolism produces a large variety of products with numerous complex biological activities. While metabolites generated by cyclooxygenase and lipoxoygenase have been well studied, less is known regarding the products generated by the cytochrome P450 (CYP) monooxygnease system. CYP epoxygenases (i.e., CYP2C, CYP2J) metabolize AA to four regioisomeric epoxyeicosatrienoic acids (5,6-, 8,9-, 11,12-, and 14,15-EETs), all of which are biologically active. Removal of EETs can occur by conjugation, chain elongation, ß-oxidation, or esterification resulting in reincorporation into phospholipid membranes. However, the predominant pathway of metabolism is the formation of less active vicinal diol compounds by epoxide hydrolases. There are two major epoxide hydrolases found in mammalian tissues, microsomal epoxide hydrolase (mEH) and soluble epoxide hydrolase (sEH or EPHX2).
Accumulating evidence indicates that endogenously produced EETs have important functional roles as both autocrine and paracrine lipid mediators. EET-mediated events will act locally to improve or resolve altered cellular homeostasis. While several groups are intensely investigating a potential EET receptor, experimental evidence shows that they affect biological processes such as; vascular tone, inflammation, analgesia and fibrosis as well elicit protective effects in conditions like hypertension, diabetes and ischemia reperfusion. Inhibitors of sEH, which raise endogenous EET levels, have been evaluated in clinical trials as anti-hypertensive agents and are being considered for long-term use in a variety of chronic medical conditions. In contrast, emerging research indicates EETs have a role in cancer biology where they may control cell-autonomous as well as non-cell-autonomous processes. Because of their role in promoting tumor cell proliferative and migration, antiapoptotic and angiogenesis stimulating activities, as well as their pharmacological accessibility, EETs have attracted interests as target for anticancer therapy. Thus, due to the organ protective and cancer promoting effects of EETs, these lipid mediators appear to function as a double-edged sword in the regulation of health and disease. Consequently, EET agonists or antagonists may, depending on the context, be a beneficial therapeutic strategy in various diseases. Thus, EET agonists and/or antagonists are potentially double-edged swords in cardiovascular diseases and cancer therapy. The rapid development of research tools, such as synthetic agonists, antagonists and enzyme inhibitors provide tools to dissect the molecular, cellular and biological pathways unraveling the mechanism and potential therapeutic targets.
In the present Frontiers Research Topic we address one of the evolving questions in the field EETs: In what context are EETs beneficial or detrimental? This Research Topic dedicated to EETs in health and disease will hopefully shed light onto the broadening front of research in this multifaceted problem. We encourage authors to present original research articles, reviews, or minireviews that will stimulate the continuing efforts in understanding the role of EETs in health and disease. Studies that evaluate the cellular and other mechanisms linking EETs in health and diseases are also welcome. Reviews that survey the pleiotropic and complex effects of EETs, their agonists/antagonists and inducers/inhibitors of their metabolism will be of great utility to the growing community of EET researchers. We encourage colleagues to contribute their findings and perspectives on EETs from the molecular to the cellular level, at the tissue and organ levels dealing with how EETs beneficially or detrimentally affect function in health and disease.
Arachidonic acid (AA) metabolism produces a large variety of products with numerous complex biological activities. While metabolites generated by cyclooxygenase and lipoxoygenase have been well studied, less is known regarding the products generated by the cytochrome P450 (CYP) monooxygnease system. CYP epoxygenases (i.e., CYP2C, CYP2J) metabolize AA to four regioisomeric epoxyeicosatrienoic acids (5,6-, 8,9-, 11,12-, and 14,15-EETs), all of which are biologically active. Removal of EETs can occur by conjugation, chain elongation, ß-oxidation, or esterification resulting in reincorporation into phospholipid membranes. However, the predominant pathway of metabolism is the formation of less active vicinal diol compounds by epoxide hydrolases. There are two major epoxide hydrolases found in mammalian tissues, microsomal epoxide hydrolase (mEH) and soluble epoxide hydrolase (sEH or EPHX2).
Accumulating evidence indicates that endogenously produced EETs have important functional roles as both autocrine and paracrine lipid mediators. EET-mediated events will act locally to improve or resolve altered cellular homeostasis. While several groups are intensely investigating a potential EET receptor, experimental evidence shows that they affect biological processes such as; vascular tone, inflammation, analgesia and fibrosis as well elicit protective effects in conditions like hypertension, diabetes and ischemia reperfusion. Inhibitors of sEH, which raise endogenous EET levels, have been evaluated in clinical trials as anti-hypertensive agents and are being considered for long-term use in a variety of chronic medical conditions. In contrast, emerging research indicates EETs have a role in cancer biology where they may control cell-autonomous as well as non-cell-autonomous processes. Because of their role in promoting tumor cell proliferative and migration, antiapoptotic and angiogenesis stimulating activities, as well as their pharmacological accessibility, EETs have attracted interests as target for anticancer therapy. Thus, due to the organ protective and cancer promoting effects of EETs, these lipid mediators appear to function as a double-edged sword in the regulation of health and disease. Consequently, EET agonists or antagonists may, depending on the context, be a beneficial therapeutic strategy in various diseases. Thus, EET agonists and/or antagonists are potentially double-edged swords in cardiovascular diseases and cancer therapy. The rapid development of research tools, such as synthetic agonists, antagonists and enzyme inhibitors provide tools to dissect the molecular, cellular and biological pathways unraveling the mechanism and potential therapeutic targets.
In the present Frontiers Research Topic we address one of the evolving questions in the field EETs: In what context are EETs beneficial or detrimental? This Research Topic dedicated to EETs in health and disease will hopefully shed light onto the broadening front of research in this multifaceted problem. We encourage authors to present original research articles, reviews, or minireviews that will stimulate the continuing efforts in understanding the role of EETs in health and disease. Studies that evaluate the cellular and other mechanisms linking EETs in health and diseases are also welcome. Reviews that survey the pleiotropic and complex effects of EETs, their agonists/antagonists and inducers/inhibitors of their metabolism will be of great utility to the growing community of EET researchers. We encourage colleagues to contribute their findings and perspectives on EETs from the molecular to the cellular level, at the tissue and organ levels dealing with how EETs beneficially or detrimentally affect function in health and disease.