Carlos Hernández1,2, Maria Dolores Barrachina3, Jorge Vallecillo-Hernández3, Ángeles Álvarez3,4, Dolores Ortiz-Masiá3, Jesús Cosín-Roger3, Juan Vicente Esplugues3,5, Sara Calatayud3. 1. Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain. carlos.hernandez-saez@uv.es. 2. FISABIO, Hospital Dr. Peset, Av. Cataluña, 21, 46020, Valencia, Spain. carlos.hernandez-saez@uv.es. 3. Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain. 4. Fundación General Universidad de Valencia, Calle Amadeo de Saboya, 4, 46010, Valencia, Spain. 5. FISABIO, Hospital Dr. Peset, Av. Cataluña, 21, 46020, Valencia, Spain.
Abstract
BACKGROUND: Aspirin (ASA) causes gastrotoxicity by hampering the epithelial defense against luminal contents through cyclooxygenase inhibition. Since cell survival in tough conditions may depend on rescue mechanisms like autophagy, we analyzed whether epithelial cells rely on this process to defend themselves from aspirin's damaging action. METHODS: Rats received a single dose of ASA (150 mg/kg, p.o.) with or without pretreatment with the autophagy inhibitor 3-methyladenine, and gastric injury and epithelial autophagy were evaluated 3 h later. The effects of ASA on cell viability and autophagy were also evaluated in gastric epithelial AGS cells. RESULTS: Basal autophagy in the gastric mucosa was inhibited by ASA as demonstrated by increased levels of p62 and ubiquitinated proteins and total LC3 and a reduced LC3-II/LC3-I ratio. Similarly, ASA increased p62 and decreased LC3-II accumulation and the number of EmGFP/LC3B puncta in AGS cells. ASA activated the PI3K/Akt-GSK3-mTOR pathway, which phosphorylates ULK1 to prevent autophagy initiation, changes that were inhibited by the PI3K-inhibitor wortmannin. Autophagy inhibition seems to enhance the vulnerability of gastric epithelial cells as a combination of ASA with 3-methyladenine exacerbated rat gastric damage and AGS cell apoptosis. CONCLUSIONS: Our data highlight the importance of autophagy in the gastric mucosa as a protective mechanism when the epithelium is injured. In the stomach, aspirin induces mucosal damage and reduces autophagy, thus, eliminating a protective mechanism that epithelial cells could use to escape death. We hypothesize that the combination of aspirin with drugs that activate autophagy could protect against gastric damage.
BACKGROUND:Aspirin (ASA) causes gastrotoxicity by hampering the epithelial defense against luminal contents through cyclooxygenase inhibition. Since cell survival in tough conditions may depend on rescue mechanisms like autophagy, we analyzed whether epithelial cells rely on this process to defend themselves from aspirin's damaging action. METHODS:Rats received a single dose of ASA (150 mg/kg, p.o.) with or without pretreatment with the autophagy inhibitor 3-methyladenine, and gastric injury and epithelial autophagy were evaluated 3 h later. The effects of ASA on cell viability and autophagy were also evaluated in gastric epithelial AGS cells. RESULTS: Basal autophagy in the gastric mucosa was inhibited by ASA as demonstrated by increased levels of p62 and ubiquitinated proteins and total LC3 and a reduced LC3-II/LC3-I ratio. Similarly, ASA increased p62 and decreased LC3-II accumulation and the number of EmGFP/LC3B puncta in AGS cells. ASA activated the PI3K/Akt-GSK3-mTOR pathway, which phosphorylates ULK1 to prevent autophagy initiation, changes that were inhibited by the PI3K-inhibitor wortmannin. Autophagy inhibition seems to enhance the vulnerability of gastric epithelial cells as a combination of ASA with 3-methyladenine exacerbated ratgastric damage and AGS cell apoptosis. CONCLUSIONS: Our data highlight the importance of autophagy in the gastric mucosa as a protective mechanism when the epithelium is injured. In the stomach, aspirin induces mucosal damage and reduces autophagy, thus, eliminating a protective mechanism that epithelial cells could use to escape death. We hypothesize that the combination of aspirin with drugs that activate autophagy could protect against gastric damage.
Authors: Michael Overholtzer; Arnaud A Mailleux; Ghassan Mouneimne; Guillaume Normand; Stuart J Schnitt; Randall W King; Edmund S Cibas; Joan S Brugge Journal: Cell Date: 2007-11-30 Impact factor: 41.582
Authors: Farhat V N Din; Asta Valanciute; Vanessa P Houde; Daria Zibrova; Kevin A Green; Kei Sakamoto; Dario R Alessi; Malcolm G Dunlop Journal: Gastroenterology Date: 2012-03-06 Impact factor: 22.682
Authors: Sahar M Gebril; Yuko Ito; Masa-Aki Shibata; Kentaro Maemura; Eman E Abu-Dief; Mahmoud R A Hussein; Usama M Abdelaal; Hoda M Elsayed; Yoshinori Otsuki; Kazuhide Higuchi Journal: Int J Exp Pathol Date: 2020-09-28 Impact factor: 1.925