Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor.
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.
Weaver
Joel G R
JG
Division of General Surgery, University of Ottawa, Ottawa, Ontario, Canada.
Tarze
Agathe
A
Moffat
Tia C
TC
Lebras
Morgane
M
Deniaud
Aurelien
A
Brenner
Catherine
C
Bren
Gary D
GD
Morin
Mario Y
MY
Phenix
Barbara N
BN
Dong
Li
L
Jiang
Susan X
SX
Sim
Valerie L
VL
Zurakowski
Bogdan
B
Lallier
Jessica
J
Hardin
Heather
H
Wettstein
Peter
P
van Heeswijk
Rolf P G
RP
Douen
Andre
A
Kroemer
Romano T
RT
Hou
Sheng T
ST
Bennett
Steffany A L
SA
Lynch
David H
DH
Kroemer
Guido
G
Badley
Andrew D
AD
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
D000906:Antibodies; C481004:CH-11 anti-fas antibody, human; D017320:HIV Protease Inhibitors; D000226:Mitochondrial ADP, ATP Translocases; D019888:Nelfinavir; D019438:Ritonavir