title: The natural olive constituent oleuropein induces nutritional cardioprotection in normal and cholesterol-fed rabbits: comparison with preconditioning.
abstract: Ischemic preconditioning, which is mediated by cell signaling molecules, protects the heart from ischemia-reperfusion injury by limiting the infarct size. Oleuropein, the main polyphenolic constituent of olives, reduced the infarct size in normal and cholesterol-fed rabbits when it was administered at a nutritional dose. The aim of the present study was to compare the effects of oleuropein and preconditioning in terms of the cell signaling and metabolism pathways underlying myocardial protection. Rabbits were randomly divided into six groups: the control group received 5 % dextrose for six weeks, the preconditioning group was subjected to two cycles of preconditioning with 5 min ischemia/10 min reperfusion, the O6 group was treated with oleuropein for six weeks, the Chol group was fed a cholesterol-enriched diet and 5 % dextrose for six weeks, and the CholO6 and CholO3 groups were treated with cholesterol and oleuropein for six and three weeks, respectively; oleuropein was dissolved in 5 % dextrose solution and was administered orally at a dose of 20 mg × kg(-1) × day(-1). All animals were subsequently subjected to 30 min myocardial ischemia followed by 10 min of reperfusion. At that time, myocardial biopsies were taken from the ischemic areas for the assessment of oxidative and nitrosative stress biomarkers (malondialdehyde and nitrotyrosine), and determination of phosphorylation of signaling molecules involved in the mechanism of preconditioning (PI3K, Akt, eNOS, AMPK, STAT3). The tissue extracts NMR metabolic profile was recorded and further analyzed by multivariate statistics. Oxidative biomarkers were significantly reduced in the O6, CholO6, and CholO3 groups compared to the control, preconditioning, and Chol groups. Considering the underlying signaling cascade, the phosphorylation of PI3K, Akt, eNOS, AMPK, and STAT-3 was significantly higher in the preconditioning and all oleuropein-treated groups compared to the control and Chol groups. The NMR-based metabonomic study, performed through the analysis of spectroscopic data, depicted differences in the metabolome of the various groups with significant alterations in purine metabolism. In conclusion, the addition of oleuropein to a normal or hypercholesterolemic diet results in a preconditioning-like intracellular effect, eliminating the deleterious consequences of ischemia and hypercholesterolemia, followed by a decrease of oxidative stress biomarkers. This effect is exerted through inducing preconditioning-involved signaling transduction. Nutritional preconditioning may support the low cardiovascular morbidity and mortality associated with the consumption of olive products.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Andreadou
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Benaki
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Efentakis
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Sofia-Iris
authors.initials: SI
authors.lastname: Bibli
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Alkistis-Ioanna
authors.initials: AI
authors.lastname: Milioni
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Papachristodoulou
authors.affiliation: Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Zoga
authors.affiliation: Laboratory of Pharmacognosy and Chemistry of Natural Products, Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.affiliation: Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
authors.forename: Efstathios K
authors.initials: EK
authors.lastname: Iliodromitis
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000009:adverse effects; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000188:drug therapy*; D057888:Iridoid Glucosides; D039823:Iridoids / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D009206:Myocardium / Q000378:metabolism; D031658:Olea / Q000737:chemistry*; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D002784:Cholesterol; D057888:Iridoid Glucosides; D039823:Iridoids; D008315:Malondialdehyde; D019869:Phosphatidylinositol 3-Kinases; D020011:Protective Agents; D014443:Tyrosine; C002769:oleuropein; C002744:3-nitrotyrosine