miR-34a-5p Inhibition Alleviates Intestinal Ischemia/Reperfusion-Induced Reactive Oxygen Species Accumulation and Apoptosis via Activation of SIRT1 Signaling
miR-34a-5p Inhibition Alleviates Intestinal Ischemia/Reperfusion-Induced Reactive Oxygen Species Accumulation and Apoptosis via Activation of SIRT1 Signaling
复制标题
miR-34a-5p 抑制通过激活 SIRT1 信号传导减轻肠道缺血/再灌注诱导的活性氧积累和细胞凋亡。
DOI：
10.1089/ars.2015.6492
复制
发表时间：
2016-06-10
影响因子：
6.6
通讯作者：
Tian, Xiaofeng
中科院分区：
文献类型：
--
作者：
Wang, Guangzhi;Yao, Jihong;Tian, Xiaofeng
旨在
活性氧（Reactive oxygen species，ROS）的产生和大量的上皮细胞凋亡是肠缺血/再灌注（ischemia/reperfusion，I/R）损伤的重要机制。我们以前发现，在I/R后，Sirtuin 1（SIRT 1）介导的抗氧化途径在肠道中受损。在此，我们研究了SIRT 1靶向microRNAs（miRNAs）在调节肠I/R中ROS积累和细胞凋亡中的潜在作用，以及SIRT 1参与的重要作用。
结果
C57 BL/6小鼠进行肠I/R，通过阻断上级肠系膜动脉随后再灌注诱导。Caco-2细胞在缺氧/复氧条件下孵育以模拟体内I/R。我们发现SIRT 1在再灌注早期逐渐受到抑制，这种抑制导致肠道ROS积累和细胞凋亡。利用生物信息学分析和实时PCR，我们证明了miR-34 a-5 p和miR-495- 3 p在41个推定的可以靶向SIRT 1的miRNAs中显著增加。抑制miR-34 a-5 p而非miR-495- 3 p可减轻肠I/R损伤，如通过抑制p66 shc上调、锰超氧化物歧化酶抑制和胱天蛋白酶-3活化在体外和体内所证实的;其进一步减轻全身性损伤，如通过减少炎性细胞因子释放、减轻肺和肝病变以及改善存活所证实的。有趣的是，SIRT 1在miR-34 a-5 p抑制所提供的保护中起着不可或缺的作用。
创新
本研究首次提供了miRNAs在肠I/R中调节氧化应激和细胞凋亡的证据。
结论
miR-34 a-5 p敲低通过促进SIRT 1介导的上皮ROS积累和凋亡抑制来减轻肠I/R损伤。这可能代表了一种新的预防肠I/R损伤的方法。抗氧化剂。氧化还原信号。24，961-973。
AIMS
Reactive oxygen species (ROS) generation and massive epithelial apoptosis are critical in the pathogenesis of intestinal ischemia/reperfusion (I/R) injury. We previously found that the Sirtuin 1 (SIRT1)-mediated antioxidant pathway was impaired in the intestine after I/R. Here, we investigate the potential role of SIRT1-targeting microRNAs (miRNAs) in regulating ROS accumulation and apoptosis in intestinal I/R, and the important role SIRT1 involved in.
RESULTS
C57BL/6 mice were subjected to intestinal I/R induced by occlusion of the superior mesenteric artery followed by reperfusion. Caco-2 cells were incubated under hypoxia/reoxygenation condition to mimic I/R in vivo. We find that SIRT1 is gradually repressed during the early reperfusion, and that this repression results in intestinal ROS accumulation and apoptosis. Using bioinformatics analysis and real-time PCR, we demonstrate that miR-34a-5p and miR-495-3p are significantly increased among the 41 putative miRNAs that can target SIRT1. Inhibition of miR-34a-5p, but not miR-495-3p, attenuates intestinal I/R injury, as demonstrated by repressing p66shc upregulation, manganese superoxide dismutase repression, and the caspase-3 activation in vitro and in vivo; it further alleviates systemic injury, as demonstrated by reducing inflammatory cytokine release, attenuating lung and liver lesions, and improving survival. Interestingly, SIRT1 plays an indispensable role in the protection afforded by miR-34a-5p inhibition.
INNOVATION
This study provides the first evidence of miRNAs in regulating oxidative stress and apoptosis in intestinal I/R.
CONCLUSION
miR-34a-5p knockdown attenuates intestinal I/R injury through promoting SIRT1-mediated suppression of epithelial ROS accumulation and apoptosis. This may represent a novel prophylactic approach to intestinal I/R injury. Antioxid. Redox Signal. 24, 961-973.