Resveratrol inhibits autophagy against myocardial ischemia-reperfusion injury through the DJ-1/MEKK1/JNK pathway
Resveratrol inhibits autophagy against myocardial ischemia-reperfusion injury through the DJ-1/MEKK1/JNK pathway
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DOI：
10.1016/j.ejphar.2023.175748
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发表时间：
2023-05-15
影响因子：
5
通讯作者：
Chen，Heping
中科院分区：
文献类型：
--
作者：
Liu，Song;Ren，Jianmin;Chen，Heping
白藜芦醇（RES）是一种存在于红酒和葡萄皮中的天然多酚类化合物，由于其心脏保护特性而引起了人们的极大关注。DJ-1是一种参与转录调控和抗氧化防御的多功能蛋白质，在缺血再灌注处理的心肌细胞中显示出显著的保护作用。本研究通过结扎大鼠左前降支分支，使H9 c2细胞缺氧/复氧（A/R），建立大鼠心肌缺血-再灌注（I/R）模型，观察RES是否通过上调DJ-1表达减轻心肌缺血-再灌注损伤。我们发现RES显着增强了I/R大鼠的心脏功能。随后，我们发现RES在体外和体内阻止了由心脏缺血再灌注诱导的自噬（P62降解和LC 3-II/LC 3-I增加）的增加。值得注意的是，自噬激动剂雷帕霉素（RAPA）消除了RES诱导的心脏保护作用。进一步研究表明，RES能显著增加心肌缺血再灌注后DJ-1的表达。同时，RES预处理降低心肌缺血再灌注刺激的MAPK/ERK激酶激酶1（MEKK 1）和Jun N-末端激酶（JNK）的磷酸化，以及Beclin-1 mRNA和蛋白水平，同时降低乳酸脱氢酶（LDH），提高细胞活力。然而，慢病毒shDJ-1和JNK激动剂茴香霉素破坏了RES的作用。综上所述，RES可通过DJ-1调节MEKK 1/JNK通路抑制自噬，从而对抗心肌缺血再灌注损伤，为心脏稳态提供了一种新的治疗策略。
Resveratrol (RES), a natural polyphenolic compound found in red wine and grape skins, has attracted significant attention due to its cardioprotective properties. DJ-1, a multifunctional protein that participated in transcription regulation and antioxidant defense, was shown to provide a significant protective impact in cardiac cells treated with ischemia-reperfusion. We created a myocardial ischemia-reperfusion (I/R) model in vivo and in vitro by ligating the left anterior descending branch of rats and subjecting H9c2 cells to anoxia/reoxygenation (A/R) to investigate whether RES reduces myocardial ischemia-reperfusion injury by upregulating DJ-1. We discovered that RES dramatically enhanced cardiac function in rats with I/R. Subsequently, we found that RES prevented the rise in autophagy (P62 degradation and LC3-II/LC3-I increase) induced by cardiac ischemia-reperfusion in vitro and in vivo. Notably, the autophagic agonist rapamycin (RAPA) eliminated RES-induced cardioprotective effects. In addition, Further data showed that RES significantly increased the expression of DJ-1 in the myocardium with the treatment of I/R. At the same time, pretreatment with RES reduced phosphorylation of MAPK/ERK kinase kinase 1 (MEKK1) and Jun N-terminal Kinase (JNK) stimulated by cardiac ischemia-reperfusion, and Beclin-1 mRNA and protein levels while decreasing lactate dehydrogenase (LDH) and improving cell viability. However, the lentiviral shDJ-1 and JNK agonist anisomycin disrupted the effects of RES. In summary, RES could inhibit autophagy against myocardial ischemia-reperfusion injury through DJ-1 modulation of the MEKK1/JNK pathway, providing a novel therapeutic strategy for cardiac homeostasis.