title: Hypercholesterolemia abrogates late preconditioning via a tetrahydrobiopterin-dependent mechanism in conscious rabbits.
abstract: BACKGROUND
  Although the late phase of ischemic preconditioning (PC) is known to confer cardioprotection in healthy animal models, it is unknown whether this phenomenon exists in the presence of hypercholesterolemia. The goal of this study was to determine whether the infarct-sparing effect of late PC is affected by hypercholesterolemia and, if so, whether a tetrahydrobiopterin (BH4)-dependent mechanism is responsible for the loss of late PC.
  
  
  RESULTS
  Conscious rabbits fed a normal diet or a 1% cholesterol diet for 6 weeks were subjected to ischemic PC (six 4-minute coronary occlusion/4-minute reperfusion cycles) and, 24 hours later, underwent a 30-minute occlusion followed by 3 days of reperfusion. A total of 125 rabbits were used. In normocholesterolemic rabbits, ischemic PC reduced infarct size, an effect that was abrogated by administration of the BH4 synthesis inhibitor N-acetylserotonin (15 mg/kg IV) before the 30-minute occlusion. In hypercholesterolemic rabbits, however, ischemic PC failed to reduce infarct size. Myocardial BH4 levels in the ischemic zone increased 24 hours after ischemic PC in normocholesterolemic rabbits but not in hypercholesterolemic rabbits. In addition, in normocholesterolemic rabbits, pretreatment with N-acetylserotonin completely abolished the ischemic PC-induced increase in myocardial BH4 levels.
  
  
  CONCLUSIONS
  This study demonstrates that (1) hypercholesterolemia abrogates both the infarct-sparing effect of late PC and the concomitant upregulation of myocardial BH4, and (2) inhibition of myocardial BH4 synthesis in the absence of hypercholesterolemia is sufficient to abolish the infarct-sparing effect of late PC. The results support the concept that hypercholesterolemia abrogates late PC by preventing the upregulation of BH4, an essential cofactor for inducible nitric oxide synthase.
authors.affiliation: Institute of Molecular Cardiology, University of Louisville, The Jewish Hospital Heart and Lung Institute, Louisville, KY, USA.
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Tang
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takano
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Xuan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Eitaro
authors.initials: E
authors.lastname: Kodani
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhu
authors.forename: Gregg
authors.initials: G
authors.lastname: Shirk
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Wu
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002791:Cholesterol, Dietary; D003243:Consciousness; D003326:Coronary Circulation; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000503:physiopathology*; D019194:Ischemic Preconditioning; D017202:Myocardial Ischemia / Q000503:physiopathology*; D011817:Rabbits
chemical_list: D002791:Cholesterol, Dietary; D001708:Biopterins; C003402:sapropterin