Recombinant angiopoietin-like protein 4 attenuates intestinal barrier structure and function injury after ischemia/reperfusion

Abstract

BACKGROUND Intestinal barrier breakdown, a frequent complication of intestinal ischemia-reperfusion (I/R) including dysfunction and the structure changes of the intestine, is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality. To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration. Recombinant human angiopoietin-like protein 4 (rhANGPTL4) is reported to protect the blood-brain barrier when administered exogenously, and endogenous ANGPTL4 deficiency deteriorates radiation-induced intestinal injury. AIM To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R. METHODS Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion. Intestinal epithelial (Caco-2) cells and human umbilical vein endothelial cells were challenged by hypoxia/ reoxygenation to mimic I/R in vitro . RESULTS Indicators including fluorescein isothiocyanate-conjugated dextran (4 kilodaltons; FD-4) clearance, ratio of phosphorylated myosin light chain/total myosin light chain, myosin light chain kinase and loss of zonula occludens-1, claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation. rhANGPTL4 treatment significantly reversed these indicators, which were associated with inhibiting the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis and improvement of survival rate. Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation, whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly. CONCLUSION rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.

RNA sequencing reveals the potential mechanism of exercise preconditioning for cerebral ischemia reperfusion injury in rats

“…In addition, studies have indicated that TIMP1, SOCS3, ANGPTL4, CDO1, and SERPINE1 are closely associated with CIRI (Liang et al, 2021;Nie et al, 2022;Pu et al, 2022;Wang, Lin et al, 2021) and the HIF-1 pathway (Cui et al, 2015;Fujii et al, 2020;Qi et al, 2023;Warnhoff et al, 2024). Consequently, the expressions of these genes in cerebral cortical tissues were analyzed at both the mRNA and protein levels, and the results of qPCR and Western blotting revealed that EP downregulated TIMP1, SOCS3, ANGPTL4, CDO1, and SERPINE1 expressions in MCAO rats.…”

Microvascular Leakage as Therapeutic Target for Ischemia and Reperfusion Injury

“…Recombinant ANGPTL4 reduces no-reflow, hemorrhage and infarct size after myocardial infarction in mice and rabbits [102]. It also attenuates intestinal barrier structure and function after ischemia/reperfusion [108]. Interestingly, the traditional Chinese medicine Tongxinluo is also active against myocardial IRI by stimulating the expression of ANGPTL4 [109].…”

Curcumin suppresses the Wnt/β‐catenin signaling pathway by inhibiting NKD2 methylation to ameliorate intestinal ischemia/reperfusion injury

“…4 Intestinal I/R injury induces the influx of oxygen, which triggers the overproduction of reactive oxygen species (ROS) and inflammatory reactions in the intestinal epithelium, resulting in programmed cell responses such as apoptosis, autophagy, and necroptosis. [5][6][7] These pathological responses disrupt the integrity of the intestinal mucosal barrier, which is maintained by tight junctions (TJs) and intercellular junctions, 8,9 inducing translocation of gut bacteria and endotoxins to proximal tissues or distal organs 10,11 and eventually leading to deleterious complications such as systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome. 12,13 These findings highlight the need to identify new therapeutic strategies against intestinal I/R injury.…”