Ghrelin alleviates intestinal ischemia–reperfusion injury by activating the GHSR‐1α/Sirt1/FOXO1 pathway

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.