title: Endoplasmic reticulum stress-mediated autophagy protects against lipopolysaccharide-induced apoptosis in HL-1 cardiomyocytes.
abstract: Apoptosis of cardiomyocytes limits the contractile efficiency of the heart during sepsis. Prosurvival autophagy has been proposed as a novel mechanism to maintain normal heart function. Here, we demonstrated that autophagy was activated in lipopolysaccharide (LPS)-treated HL-1 cells, and it counteracted the LPS-induced apoptosis. We investigated further the mechanism by which LPS triggered autophagy in HL-1 cells. We discovered that endoplasmic reticulum (ER) stress played an important role in LPS-triggered autophagy. The ER activated a survival pathway through the ER-localized transmembrane protein PERK, which was essential for LPS-induced autophagy. Lipopolysaccharide increased expression of GRP78, phosphorylated PERK and phosphorylated eukaryotic initiation factor 2α. Similar results were observed after administration of tunicamycin, a well-known ER stressor. Most importantly, we found that 4-phenylbutyrate, an inhibitor of ER stress, suppressed LPS-activated autophagy in the presence of LPS in HL-1 cells. The same results were observed after small interfering RNA-mediated silencing of PERK protein. We also noticed that LPS-induced apoptosis appeared early, at 4 h. Our findings revealed that PERK, one arm of ER stress, facilitated survival of LPS-treated HL-1 cells by promoting autophagy, and could serve as a potential therapeutic strategy to alleviate septic myocardial dysfunction.
authors.affiliation: Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China Department of Anesthesiology, Daqing Oilfield General Hospital, Daqing, Heilongjiang, PR China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Shanglong
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Laboratory of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China leyang66@yahoo.com.
authors.forename: Le
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species