title: Ketone bodies upregulate endothelial connexin 43 (Cx43) gap junctions.
abstract: Ketosis occurs as a metabolic consequence of negative energy balance in post-calving lactating dairy cows. Metabolism of free fatty acids, released from adipose tissue, generates excessive amounts of acetoacetate (AcAc), β-hydroxybutyrate (BHB), and acetone (Ac) in the liver, which are released into the blood. The effects of ketone bodies on endothelial cells include increased rates of portal vein and liver blood flow and decreased cytokine secretion in response to both bacterial and viral infections. The aim of the current study was to understand the effects of AcAc, BHB and Ac, on expression of connexin 43 (Cx43) and gap junctional intercellular coupling (GJIC) in bovine aortic endothelial cells (BAECs). Confocal microscopy, Western blotting, and real-time quantitative RT-PCR indicated that Cx43 mRNA and protein expression increased after endothelial cell exposure to ketone bodies and that this was accompanied by upregulation of GJIC and cell migration. These effects were most obvious when BAECs were treated with a combination of the three ketones. Ketone bodies were shown to activate ERK and p38 MAPK as early as 3h after treatment and an ERK inhibitor (PD98059) or p38 MAPK inhibitor (SB203580) were found to antagonise the ketone-induced increase in Cx43 protein expression. Thus, ketone bodies up-regulate Cx43 expression and GJIC in BAECs via activation of ERK and p38 MAPK.
authors.affiliation: Department of Veterinary Medicine, National Chung Hsing University, 250 Road Kuo Kuang, Taichung 402, Taiwan.
authors.forename: Chia-Fang
authors.initials: CF
authors.lastname: Ho
authors.forename: Kun-Wei
authors.initials: KW
authors.lastname: Chan
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Yeh
authors.forename: James
authors.initials: J
authors.lastname: Kuo
authors.forename: Hung-Jen
authors.initials: HJ
authors.lastname: Liu
authors.forename: Chi-Young
authors.initials: CY
authors.lastname: Wang
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000090:Acetoacetates / Q000378:metabolism; D000096:Acetone / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D015153:Blotting, Western / Q000662:veterinary; D002417:Cattle / Q000235:genetics / Q000502:physiology*; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D017629:Gap Junctions / Q000235:genetics* / Q000378:metabolism; D007662:Ketosis / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000662:veterinary; D016133:Polymerase Chain Reaction / Q000662:veterinary; D015854:Up-Regulation
chemical_list: D000090:Acetoacetates; D018031:Connexin 43; D000096:Acetone; C016635:acetoacetic acid; D020155:3-Hydroxybutyric Acid
keywords: Cell migration; Endothelial cells; Gap junction; Ketone body; Ketosis