Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors

Abstract

The arachidonic acid cascade is arguably the most widely known biologic regulatory pathway. Decades after the seminal discoveries involving its cyclooxygenase and lipoxygenase branches, studies of this cascade remain an active area of research. The third and less widely known branch, the cytochrome P450 pathway leads to highly active oxygenated lipid mediators, epoxy fatty acids (EpFAs) and hydroxyeicosatetraenoic acids (HETEs), which are of similar potency to prostanoids and leukotrienes. Unlike the COX and LOX branches, no pharmaceuticals currently are marketed targeting the P450 branch. However, data support therapeutic benefits from modulating these regulatory lipid mediators. This is being approached by stabilizing or mimicking the EpFAs or even by altering the diet. These approaches lead to predominantly beneficial effects on a wide range of apparently unrelated states resulting in an enigma of how this small group of natural chemical mediators can have such diverse effects. EpFAs are degraded by soluble epoxide hydrolase (sEH) and stabilized by inhibiting this enzyme. In this review, we focus on interconnected aspects of reported mechanisms of action of EpFAs and inhibitors of soluble epoxide hydrolase (sEHI). The sEHI and EpFAs are commonly reported to maintain homeostasis under pathological conditions while remaining neutral under normal physiological conditions. Here we provide a conceptual framework for the unique and broad range of biological activities ascribed to epoxy fatty acids. We argue that their mechanism of action pivots on their ability to prevent mitochondrial dysfunction, to reduce subsequent ROS formation and to block resulting cellular signaling cascades, primarily the endoplasmic reticulum stress. By stabilizing the mitochondrial – ROS – ER stress axis, the range of activity of EpFAs and sEHI display an overlap with the disease conditions including diabetes, fibrosis, chronic pain, cardiovascular and neurodegenerative diseases, for which the above outlined mechanisms play key roles.

Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

“…After MIA. It is reported that the sEH inhibitor attenuates activation of the ER (26,(42)(43)(44). In this study, we examined the effects of TPPU on ER stress in the brain regions from juvenile offspring after MIA.…”

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

“…EETs also activate nuclear erythroid-related factor 2 (Nrf2), which induces the expression of antioxidant proteins and enzymes. At the cellular level, EETs are postulated to maintain ER-mitochondria homeostasis and limit reactive oxygen species formation by modulating the ER stress response and maintaining mitochondrial function (Inceoglu et al, 2017). …”

“…Its expression may be enhanced by different cellular stresses, including ER stress, thereby attenuating EETs’ protective actions (Inceoglu et al, 2017; Inceoglu et al, 2015; Mak et al, 2017). Accumulating evidence has shown that salubrinal, an agent that limits ER stress by enhancing the unfolded protein response, has protective effects on the BBB in ischemic stroke by blocking the progression of the inflammatory response that is linked to microglial reactivity and production of MMP9 (Anuncibay-Soto et al, 2018).…”

Pharmacological inhibition of soluble epoxide hydrolase as a new therapy for Alzheimer’s Disease

“…It is known that the ER stress plays a role in the pathogenesis of neurodegenerative disease, including AD (33), and those sEH inhibitors attenuate activation of the ER stress response (10). Therefore, we measured the levels of the ER stress sensors ATF-6 and IRE1α (Fig.…”

“…Epoxyeicosatrienoic acids (EETs) mediate vasodilatation, reduce inflammation, attenuate OS and block the pathological endoplasmic reticulum (ER) stress response (10,11). The soluble epoxide hydrolase enzyme (sEH, EC 3.3.2.10, EPHX2), widely expressed in relatively high abundance in the murine and human brains (12,13), converts EETs and other epoxyfatty acids (EpFA) to their corresponding dihydroxyeicosatrienoic acids (DHETs), whereby diminishing, eliminating, or altering the beneficial effects of EETs (14) (Fig.…”