title: Long-term consumption of an obesogenic high fat diet prior to ischemia-reperfusion mediates cardioprotection via Epac1-dependent signaling.
abstract: BACKGROUND
  Obesity is still considered a risk factor for cardiovascular disease, although more recent knowledge also suggests obesity to be associated with reduced morbidity and mortality - the "obesity paradox". This study explores if long-term feeding of an obesogenic high fat diet renders the myocardium less susceptible to ischemic-reperfusion induced injury via Epac-dependent signaling.
  
  
  METHODS
  Wild type (wt), Epac1 (Epac1-/-) and Epac2 (Epac2-/-) deficient mice were fed a high fat (HFD) or normal chow diet (ND) for 33 ± 1 weeks. Six experimental groups were included: (1) control wt ND (wtND), (2) control wt HFD (wtHFD), (3) Epac1-/-mice on ND (Epac1-/-ND), (4) Epac1-/-mice on HFD (Epac1-/-HFD), (5) Epac2-/-mice on ND (Epac2-/-ND), and (6) Epac2-/-mice on HFD (Epac2-/-HFD). Isolated ex vivo mice hearts were perfused in a constant pressure Langendorff mode, and exposed to 30min of global ischemia (GI) and 60min of reperfusion. Endpoints were infarct size and functional recovery.
  
  
  RESULTS
  All groups fed a HFD presented with significantly enhanced body weight, visceral fat content and reduced glucose clearance compared to corresponding ND groups. Although the HFD cohorts presented with an overall comparable systemic capability to clear glucose, the Epac1-/-HFD group presented with glucose levels slightly above the human diabetes criteria at the end of the intraperitoneal glucose tolerance test (ipGTT). Moreover, the HFD significantly reduced infarct size in both wild type (wtHFD41.3 ± 5.5% vs. wtND58.0 ± 9.8%,p< 0.05) and Epac2-/-cohorts (Epac2-/-HFD34.4 ± 7.2% vs. Epac2-/-ND56.5 ± 3.8%,p< 0.05). Interestingly, however, the HFD did not reduce infarct size in Epac1-/-deficient mice hearts (Epac1-/-HFD65.1 ± 5.1% vs. Epac1-/-ND56.1 ± 3.5%, ns.).
  
  
  CONCLUSIONS
  Epac1-dependent signaling is involved in mediating the cardioprotection afforded by long-term feeding of an obesogenic high fat diet in mice hearts.
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: F
authors.initials: F
authors.lastname: Edland
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Wergeland
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Kopperud
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: K S
authors.initials: KS
authors.lastname: Åsrud
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: E A
authors.initials: EA
authors.lastname: Hoivik
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: S L
authors.initials: SL
authors.lastname: Witsø
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Æsøy
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark ; National Institute of Nutrition and Seafood Research, Bergen, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Madsen
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Bakke
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: S O
authors.initials: SO
authors.lastname: Døskeland
authors.affiliation: Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway ; Faculty of Health Science and Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
authors.forename: A K
authors.initials: AK
authors.lastname: Jonassen
keywords: Cardiac function; Epac; Heart; High fat diet; Infarct size; Myocardial ischemia; Obesity; PKA; Reperfusion injury; cAMP