Abstract
Activation of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome cascade has a role in the pathogenesis of ischemia/reperfusion (IR) injury. There is growing evidence indicating cytochrome p450 (CYP450)-derived metabolites of n-3 and n-6 polyunsaturated fatty acids (PUFAs) possess both adverse and protective effects in the heart. CYP-derived epoxy metabolites are rapidly hydrolyzed by the soluble epoxide hydrolase (sEH). The current study hypothesized that the cardioprotective effects of inhibiting sEH involves limiting activation of the NLRP3 inflammasome. Isolated hearts from young wild-type (WT) and sEH null mice were perfused in the Langendorff mode with either vehicle or the specific sEH inhibitor t-AUCB. Improved post-ischemic functional recovery and better mitochondrial respiration were observed in both sEH null hearts or WT hearts perfused with t-AUCB. Inhibition of sEH markedly attenuated the activation of the NLRP3 inflammasome complex and limited the mitochondrial localization of the fission protein dynamin-related protein-1 (Drp-1) triggered by IR injury. Cardioprotective effects stemming from the inhibition of sEH included preserved activities of both cytosolic thioredoxin (Trx)-1 and mitochondrial Trx-2 antioxidant enzymes. Together, these data demonstrate that inhibiting sEH imparts cardioprotection against IR injury via maintaining post-ischemic mitochondrial function and attenuating a detrimental innate inflammatory response.
Highlights
Ischemic heart disease is a leading cause of cardiovascular death and disability worldwide [1,2]
Accumulating literature suggests that soluble epoxide hydrolase (sEH) enzyme is a good target to ameliorate IR injury [24,26,30], the differential response of both males and females to sEH inhibition has not been investigated
Preischemic cardiac parameters were similar between males and females in all young treatment groups. sEH null hearts or WT hearts perfused with the sEH inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) and subjected to IR showed significantly improved post-ischemic recovery of left ventricular developed pressure (LVDP) compared to the WT IR control group (Figure 1A)
Summary
Ischemic heart disease is a leading cause of cardiovascular death and disability worldwide [1,2]. Experimental evidence has demonstrated that during reperfusion a surge of reactive oxygen species (ROS) is rapidly generated from damaged mitochondria This ROS burst triggers a series of inflammatory reactions, which induce the formation and activation of inflammasomes aggravating myocardial injury [6,7,8]. The detrimental outcomes associated with the activation of sEH in response to cardiovascular insult could be attributed to the excessive degradation of protective epoxylipids (i.e., EDPs and EETs) and enhanced production of toxic diol-metabolites (i.e., DiHOMEs). Results from the current study builds upon our previous findings [28,29] and demonstrates that deletion of the gene encoding sEH (Ephx2) or pharmacological inhibition of sEH enzyme could attenuate myocardial IR injury through maintaining mitochondrial function and limiting NLRP3 inflammasome activation. To the best of our knowledge, the current study provides the first evidence that the cardioprotective effects associated with sEH inhibition against IR injury is sex-independent in young subjects
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