Faculty of Pharmacy and Pharmaceutical Sciences, 2026-M Katz Group Centre for Pharmacy and Health Research, University of Alberta, 11361-97 Ave, Edmonton, AB T6G 2E1, Canada.
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Int J Mol Sci. 2020 Jul 24;21(15):5261. doi: 10.3390/ijms21155261.
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.
虽然心脏缺血再灌注（IR）损伤后的存活率有了显著提高，但由此产生的心脏损伤仍然是一个重要问题。维持线粒体质量和限制 NLRP3 炎性小体的激活是限制 IR 损伤的一种方法，其中线粒体去乙酰化酶 SIRT3 发挥作用。最近的数据表明，二十二碳六烯酸（DHA）的细胞色素 P450（CYP450）衍生的环氧化物代谢物，环氧二十二碳五烯酸（EDPs），可减轻心脏 IR 损伤。EDPs 会通过酶和非酶过程迅速被清除和失活。本研究假设合成 EDP 类似物 AS-27、SA-26 和 AA-4 对 IR 损伤的心脏保护作用涉及 SIRT3 的激活。用载体、AS-27、SA-26 或 AA-4 对野生型（WT）小鼠的离体心脏进行 Langendorff 模式灌注。与对照组相比，用类似物 SA-26 灌注的心脏在缺血后功能恢复得到改善，心脏 ATP 水平维持，氧化应激减少，NLRP3 激活减弱。对心脏线粒体的评估表明，SA-26 可维持 SIRT3 活性，减少锰超氧化物歧化酶（MnSOD）的乙酰化，表明其抗氧化能力增强。总之，这些数据表明，EDP 类似物 SA-26 对 IR 损伤的心脏保护作用涉及到维持线粒体 SIRT3 的活性，从而减轻了有害的先天 NLRP3 炎性小体反应。
