title: Food supplementation with rice bran enzymatic extract prevents vascular apoptosis and atherogenesis in ApoE-/- mice.
abstract: OBJECTIVE
  Atherosclerosis is associated with reduced mononuclear cell (MNC) telomere length, and senescent cells have been detected in atherosclerotic plaques. Rice bran is a source of γ-oryzanol, phytosterols and tocols with potential lipid-lowering, antioxidant and anti-inflammatory activities. Here, we tested the hypothesis that rice bran enzymatic extract (RBEE) impacts on apoptosis, telomere length and atherogenesis in mice.
  
  
  METHODS
  Seven-week-old male ApoE-/- mice were fed high-fat diet (HFD) or isocaloric HFD supplemented with 5 % (w/w) RBEE for 23 weeks. Wild-type mice of the same age were kept under standard diet as controls.
  
  
  RESULTS
  RBEE treatment reduced total cholesterol (19.24 ± 1.63 vs 24.49 ± 1.71 mmol/L) and triglycerides (1.13 ± 0.18 vs 1.75 ± 0.22 mmol/L) and augmented HDL-cholesterol (1.86 ± 0.20 vs 1.07 ± 0.20 mmol/L). RBEE attenuated macrophage infiltration by 56.69 ± 4.65 % and plaque development (7737 ± 836 vs 12,040 ± 1001 μm2) in the aortic sinus. In the aorta, RBEE treatment reduced expression of the apoptosis pathway components p16, p53 and bax/bcl-2 ratio. RBEE prevented apoptosis of aortic endothelial cells (2.81 ± 0.71-1.14 ± 0.35 apoptotic nuclei/ring for ApoE-/- HFD and ApoE-/- HFD 5 % RBEE, respectively). In contrast, MNC of RBEE-fed mice exhibited enhanced apoptosis marker expression with increased p53 and bax/bcl-2 protein levels. Compared to WT, ApoE-/- mice on HFD were characterized by significant telomere shortening in aorta (11 ± 2 %) and MNC (73 ± 7 %), which was reduced by supplementation with RBEE (aorta: 40 ± 7 %; MNC: 105 ± 10 %). Expression of telomere repeat-binding factor 2 was increased in RBEE-fed mice.
  
  
  CONCLUSIONS
  Long-term food supplementation with RBEE lowers cholesterol and prevents atherosclerotic plaque development in ApoE-/- mice. Differential regulation of vascular and MNC apoptosis and senescence were identified as potential mechanisms.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Seville, C/Profesor García González 2, 41012, Seville, Spain. cpternero@us.es.
authors.forename: C
authors.identifier: http://orcid.org/0000-0002-2349-0642
authors.initials: C
authors.lastname: Perez-Ternero
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Seville, C/Profesor García González 2, 41012, Seville, Spain.
authors.forename: M D
authors.initials: MD
authors.lastname: Herrera
authors.affiliation: Klinik für Innere Medizin III - Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Laufs
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Seville, C/Profesor García González 2, 41012, Seville, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Alvarez de Sotomayor
authors.affiliation: Klinik für Innere Medizin III - Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Werner
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000517:prevention & control*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D004043:Dietary Fiber / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012275:Oryza / Q000201:enzymology*; D010666:Phenylpropionates / Q000494:pharmacology; D010840:Phytosterols / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic / Q000517:prevention & control; D014280:Triglycerides / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004043:Dietary Fiber; D010666:Phenylpropionates; D010840:Phytosterols; D010936:Plant Extracts; D014280:Triglycerides; C013172:gamma-oryzanol
keywords: ApoE−/−; Apoptosis; Atherosclerosis; Inflammation; Rice bran enzymatic extract; Telomeres