title: Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor.
abstract: Inhibitors of HIV protease have been shown to have antiapoptotic effects in vitro, yet whether these effects are seen in vivo remains controversial. In this study, we have evaluated the impact of the HIV protease inhibitor (PI) nelfinavir, boosted with ritonavir, in models of nonviral disease associated with excessive apoptosis. In mice with Fas-induced fatal hepatitis, Staphylococcal enterotoxin B-induced shock, and middle cerebral artery occlusion-induced stroke, we demonstrate that PIs significantly reduce apoptosis and improve histology, function, and/or behavioral recovery in each of these models. Further, we demonstrate that both in vitro and in vivo, PIs block apoptosis through the preservation of mitochondrial integrity and that in vitro PIs act to prevent pore function of the adenine nucleotide translocator (ANT) subunit of the mitochondrial permeability transition pore complex.
authors.affiliation: Division of General Surgery, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Joel G R
authors.initials: JG
authors.lastname: Weaver
authors.forename: Agathe
authors.initials: A
authors.lastname: Tarze
authors.forename: Tia C
authors.initials: TC
authors.lastname: Moffat
authors.forename: Morgane
authors.initials: M
authors.lastname: Lebras
authors.forename: Aurelien
authors.initials: A
authors.lastname: Deniaud
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bren
authors.forename: Mario Y
authors.initials: MY
authors.lastname: Morin
authors.forename: Barbara N
authors.initials: BN
authors.lastname: Phenix
authors.forename: Li
authors.initials: L
authors.lastname: Dong
authors.forename: Susan X
authors.initials: SX
authors.lastname: Jiang
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Sim
authors.forename: Bogdan
authors.initials: B
authors.lastname: Zurakowski
authors.forename: Jessica
authors.initials: J
authors.lastname: Lallier
authors.forename: Heather
authors.initials: H
authors.lastname: Hardin
authors.forename: Peter
authors.initials: P
authors.lastname: Wettstein
authors.forename: Rolf P G
authors.initials: RP
authors.lastname: van Heeswijk
authors.forename: Andre
authors.initials: A
authors.lastname: Douen
authors.forename: Romano T
authors.initials: RT
authors.lastname: Kroemer
authors.forename: Sheng T
authors.initials: ST
authors.lastname: Hou
authors.forename: Steffany A L
authors.initials: SA
authors.lastname: Bennett
authors.forename: David H
authors.initials: DH
authors.lastname: Lynch
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Badley
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006505:Hepatitis / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D019888:Nelfinavir / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D012772:Shock, Septic / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000473:pathology
chemical_list: D000906:Antibodies; C481004:CH-11 anti-fas antibody, human; D017320:HIV Protease Inhibitors; D000226:Mitochondrial ADP, ATP Translocases; D019888:Nelfinavir; D019438:Ritonavir