Abstract：
Ischemia-reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia-reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 μg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.
摘要：
缺血再灌注（IR）损伤的主要特征是恢复血流灌注和对缺血组织和器官的氧供应，但矛盾的是它导致组织损伤加重。IR损伤是一个具有挑战性的病理生理过程，在临床上难以避免，并且在器官移植过程中经常发生。手术,休克复苏,和其他过程。IR损伤的主要原因包括自由基水平增加，钙超载，氧化应激，过度的炎症反应。Ghrelin是一种新发现的具有抗炎和抗凋亡作用的脑肠肽，可改善血液供应。ghrelin在肠缺血再灌注损伤中的作用及机制尚不清楚。我们假设ghrelin可以减弱IIR诱导的氧化应激和细胞凋亡。为了调查这一点，我们通过使用非侵入性动脉夹夹住小鼠肠系膜上动脉（SMA）的根部来建立IIR。在IIR手术前20分钟以50μg/kg的剂量腹膜内注射Ghrelin，和[D-Lys3]-GHRP-6在注射ghrelin前20分钟以12nmol/kg的剂量腹膜内注射。我们在Caco-2细胞中通过缺氧-复氧（HR）模拟了IIR过程，在结构和生物化学上与肠上皮细胞相似。我们的结果表明，ghrelin通过激活GHSR-1α抑制IIR/HR诱导的氧化应激和细胞凋亡。此外，发现ghrelin激活了GHSR-1α/Sirt1/FOXO1信号通路。我们进一步抑制了Sirt1，并发现Sirt1对于ghrelin介导的IIR/HR损伤的缓解至关重要。总的来说,我们的数据表明,ghrelin预处理通过与GHSR-1α结合进一步激活Sirt1,从而减少氧化应激和细胞凋亡,从而减轻IIR/HR损伤.
