A Synthetic Epoxydocosapentaenoic Acid Analogue Ameliorates Cardiac Ischemia/Reperfusion Injury: The Involvement of the Sirtuin 3–NLRP3 Pathway

Abstract

While survival rates have markedly improved following cardiac ischemia-reperfusion (IR) injury, the resulting heart damage remains an important issue. Preserving mitochondrial quality and limiting NLRP3 inflammasome activation is an approach to limit IR injury, in which the mitochondrial deacetylase sirtuin 3 (SIRT3) has a role. Recent data demonstrate cytochrome P450 (CYP450)-derived epoxy metabolites, epoxydocosapentaenoic acids (EDPs), of docosahexaenoic acid (DHA), attenuate cardiac IR injury. EDPs undergo rapid removal and inactivation by enzymatic and non-enzymatic processes. The current study hypothesizes that the cardioprotective effects of the synthetic EDP surrogates AS-27, SA-26 and AA-4 against IR injury involve activation of SIRT3. Isolated hearts from wild type (WT) mice were perfused in the Langendorff mode with vehicle, AS-27, SA-26 or AA-4. Improved postischemic functional recovery, maintained cardiac ATP levels, reduced oxidative stress and attenuation of NLRP3 activation were observed in hearts perfused with the analogue SA-26. Assessment of cardiac mitochondria demonstrated SA-26 preserved SIRT3 activity and reduced acetylation of manganese superoxide dismutase (MnSOD) suggesting enhanced antioxidant capacity. Together, these data demonstrate that the cardioprotective effects of the EDP analogue SA-26 against IR injury involve preservation of mitochondrial SIRT3 activity, which attenuates a detrimental innate NLRP3 inflammasome response.

Associations between hyperhomocysteinemia and the presence and severity of acute coronary syndrome in young adults ≤ 35 years of age

“…Bianca et al [ 33 ] suggested that HCY exerted a prothrombotic effect by enhancing platelet aggregation. Several studies also showed that HHCY might enhance the adverse effects of CAD risk factors such as essential hypertension, smoking, dyslipidemia, and diabetes mellitus [ 34 – 37 ]. These were probably related to the formation and progression of CAD in young adults.…”

New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation

“…More recently, there is growing interest in ω-3 EpFAs, namely Eicosapentaenoic acid (EPA, 20:5)-derived Epoxyeicosatetraenoic acids (EEQs) and Docosahexaenoic acid (DHA, 22:6)derived Epoxydocosapentaenoic acids (EDPs), and their synthetic analogues. [29][30][31] Thus, as a possible next step, the alkoxy-mimics of these EpFAs could also be examined, especially since EEQs and EDPs have in fact proven to be more potent than EETs in certain disease models. 32,33 26 Finally, activity of individual regioisomers within the most promising series could potentially be explored, with particular emphasis being placed on molecules with functional groups positioned at the terminal olefin, since these have generally proven to be the most biologically relevant within each of the three EpFA series.…”

“…More recently, there is growing interest in ω-3-EpFAs, namely, eicosapentaenoic acid (EPA, 20:5)-derived epoxyeicosatetraenoic acids (EEQs) and docosahexaenoic acid (DHA, 22:6)-derived epoxydocosapentaenoic acids (EDPs), and their synthetic analogues. − Thus, as a next step, the alkoxy- analogues of these EpFAs could also be examined, especially since EEQs and EDPs are more potent than EETs in certain disease models. , Moreover, activity of individual regioisomers within the most promising series should eventually be explored.…”

Proteomics Revealed That Mitochondrial Function Contributed to the Protective Effect of Herba Siegesbeckiae Against Cardiac Ischemia/Reperfusion Injury

“…NLRP3 mainly localizes in the endoplasmic reticulum in the resting state, while NLRP3 and its adaptor ASC are redistributed to the perinuclear space during inflammasome activation, where they co-localize with mitochondria-associated endoplasmic reticulum and are involved in recruiting and activating pro-caspase-1 into caspase-1 ( 5 ). The activated caspase-1 then promotes the maturation and release of interleukin (IL)-1β and IL-18, and induces the synthesis of more amount of inflammatory factors, such as IL-6 and tumor necrosis factor (TNF)-α, thus leading to an inflammatory cascade response ( 15 , 16 ). Moreover, activated caspase-1 can shear and activate Gasdermin D (GSDMD) protein, causing pyroptosis and aggravating mitochondrial damage ( 17 ).…”