Figure 7.

Schematic showing the potential roles of sEH in IR injury. Cellular injury in response to IR insult is associated with the release of polyunsaturated fatty acids (PUFAs) from the cell membrane which can be metabolized via epoxidation by cytochrome P450 (CYP450) isoenzymes to linoleic acid (LA) metabolites epoxyoctadecenoic acids (EpOMEs), which are further metabolized by sEH to dihydroxyoctadecenoic acid (DiHOMEs) with cardiotoxic effects targeting mitochondria resulting in injury. In contrast, sEH rapidly degrades the cardioprotective epoxylipids, epoxydocosapentaenoic acids (EDPs) and epoxyeicosatrienoic acids (EETs), generated from the CYP-mediated metabolism of the n-3 docosahexaenoic acid (DHA) and n-6 arachidonic acid (AA), respectively. These biologically active epoxy metabolites mediate many of the beneficial cardiovascular effects of the parent PUFAs by maintaining mitochondrial quality and reducing adverse inflammatory reactions. IR injury triggers the translocation of dynamin-related protein-1 (Drp-1) from the cytosol to the mitochondria initiating events that lead to the assembly and oligomerization of NLPR3 inflammasome. Active NLPR3 shuttles Txnip to the mitochondria aggravating mitochondrial damage as well the formation of the pro-inflammatory cytokine IL-1β triggering cardiomyocyte cell death.