title: Pathway of programmed cell death and oxidative stress induced by β-hydroxybutyrate in dairy cow abomasum smooth muscle cells and in mouse gastric smooth muscle.
abstract: The administration of exogenous β-hydroxybutyrate (β-HB), as well as fasting and caloric restriction, is a condition associated with β-HB abundance and decreased appetite in animals. Increased β-HB and decreased appetite exist simultaneously in some diseases, such as bovine left displaced abomasums (LDA) and human chronic gastritis. However, the effects of β-HB on stomach injuries have not been explored. To elucidate the possible effects of exogenous β-HB on the stomach, mice were injected intraperitoneally with β-HB, and bovine abomasum smooth muscle cells (BSMCs) were treated with different concentrations of β-HB. We found that β-HB induced BSMCs endoplasmic reticulum- and mitochondria-mediated apoptotic cell death. β-HB promoted Bax expression and caspase-12, -9, and -3 activation while blocking Bcl-2 expression. β-HB also promoted AIF, EndoG release and p53 expression. β-HB acted on key molecules in the apoptotic cell death pathway and increased p38 and c-June NH2-terminal kinase phosphorylation while inhibiting ERK phosphorylation and PCNA expression. β-HB upregulated P27 and P21 mRNA levels while downregulating cyclin and CDK mRNA levels, arresting the cell cycle. These results suggest that BSMCs treated with β-HB can induce oxidative stress, which can be prevented by intracellular calcium chelators BAPTA/AM but not antioxidant NAC. Additionally, these results suggest that β-HB causes ROS generation through a Ca2+-dependent mechanism and that intracellular Ca2+ levels play a critical role in β-HB -induced apoptotic cell death. The impact of β-HB on programmed cell death and oxidative stress in vivo was confirmed in murine experiments. For the first time, we show oxidative stress effects of β-HB on smooth muscle. We propose that β-HB is a possible cause of some stomach diseases, including bovine LDA.
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Wulin
authors.initials: W
authors.lastname: Tian
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Wei
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Naisheng
authors.initials: N
authors.lastname: Zhang
authors.affiliation: College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Xie
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000633:toxicity*; D000018:Abomasum / Q000166:cytology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002478:Cells, Cultured; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013270:Stomach / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016213:Cyclins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D002118:Calcium; D020155:3-Hydroxybutyric Acid