title: Vasa vasorum anti-angiogenesis through H₂O₂, HIF-1α, NF-κB, and iNOS inhibition by mangosteen pericarp ethanolic extract (Garcinia mangostana Linn) in hypercholesterol-diet-given Rattus norvegicus Wistar strain.
abstract: BACKGROUND
  Oxidative stress in atherosclerosis produces H2O2 and triggers the activation of nuclear factor kappa beta (NF-κB) and increase of inducible nitric oxide synthase (iNOS). The formation of vasa vasorum occurs in atherosclerosis. Vasa vasorum angiogenesis is mediated by VEGFR-1 and upregulated by hypoxia-inducible factor-1α (HIF-1α). The newly formed vasa vasorum are fragile and immature and thus increase plaque instability. It is necessary to control vasa vasorum angiogenesis by using mangosteen pericarp antioxidant. This study aims to demonstrate that mangosteen pericarp ethanolic extract can act as vasa vasorum anti-angiogenesis through H2O2, HIF-1α, NF-κB, and iNOS inhibition in rats given a hypercholesterol diet.
  
  
  METHODS
  This was a true experimental laboratory, in vivo posttest with control group design, with 20 Rattus norvegicus Wistar strain rats divided into five groups (normal group, hypercholesterol group, and hypercholesterol groups with certain doses of mangosteen pericarp ethanolic extract: 200, 400, and 800 mg/kg body weight). The parameters of this study were H2O2 measured by using colorimetric analysis, as well as NF-κB, iNOS, and HIF-1α, which were measured by using immunofluorescence double staining and observed with a confocal laser scanning microscope in aortic smooth muscle cell. The angiogenesis of vasa vasorum was quantified from VEGFR-1 level in aortic tissue and confirmed with hematoxylin and eosin staining.
  
  
  RESULTS
  Analysis of variance test and Pearson's correlation coefficient showed mangosteen pericarp ethanolic extract had a significant effect (P<0.05) in decreasing vasa vasorum angiogenesis through H2O2, HIF-1α, NF-κB, and iNOS inhibition in hypercholesterol-diet-given R. norvegicus Wistar strain.
  
  
  CONCLUSIONS
  Mangosteen pericarp ethanolic extract 800 mg/kg body weight is proven to decrease vasa vasorum angiogenesis. Similar studies with other inflammatory parameters are encouraged to clarify the mechanism of vasa vasorum angiogenesis inhibition by mangosteen pericarp ethanolic extract.
authors.affiliation: Department of Biomedical, Medical Faculty, Brawijaya University, Malang, Indonesia.
authors.forename: Titin Andri
authors.initials: TA
authors.lastname: Wihastuti
authors.affiliation: Department of Cardiology, Medical Faculty, Brawijaya University, Malang, Indonesia.
authors.forename: Djanggan
authors.initials: D
authors.lastname: Sargowo
authors.affiliation: Department of Endocrinology, Medical Faculty, Airlangga University, Surabaya, Indonesia.
authors.forename: Askandar
authors.initials: A
authors.lastname: Tjokroprawiro
authors.affiliation: Department of Pharmacology, Medical Faculty, Brawijaya University, Malang, Indonesia.
authors.forename: Nur
authors.initials: N
authors.lastname: Permatasari
authors.affiliation: Department of Pharmacology, Medical Faculty, Brawijaya University, Malang, Indonesia.
authors.forename: Mohammad Aris
authors.initials: MA
authors.lastname: Widodo
authors.affiliation: Department of Pharmacology, Medical Faculty, Brawijaya University, Malang, Indonesia.
authors.forename: Setyowati
authors.initials: S
authors.lastname: Soeharto
mesh_terms: D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002791:Cholesterol, Dietary; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015536:Down-Regulation; D000431:Ethanol / Q000737:chemistry*; D029762:Garcinia mangostana / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D012997:Solvents / Q000737:chemistry*; D014651:Vasa Vasorum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D002791:Cholesterol, Dietary; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D010936:Plant Extracts; D012997:Solvents; D000431:Ethanol; D006861:Hydrogen Peroxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: H2O2; HIF-1α; NF-κB; hypercholesterol; mangosteen pericarp ethanolic extract; vasa vasorum angiogenesis