1. Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor
- Author
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Heather Hardin, Rolf P. G. van Heeswijk, Andrew D. Badley, Joel G.R. Weaver, Bogdan Zurakowski, Valerie L. Sim, Sheng T. Hou, Barbara N. Phenix, Peter J. Wettstein, Guido Kroemer, Catherine Brenner, Aurélien Deniaud, Agathe Tarze, Gary D. Bren, Morgane LeBras, Li Dong, Jessica Lallier, Andre G. Douen, Romano T. Kroemer, Tia C. Moffat, David H. Lynch, Susan X. Jiang, Mario Y. Morin, Steffany A. L. Bennett, Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and Begue, Angelique
- Subjects
Models, Molecular ,medicine.medical_treatment ,Apoptosis ,Pharmacology ,Antibodies ,Hepatitis ,Jurkat Cells ,Mice ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,In vivo ,medicine ,Animals ,Humans ,HIV Protease Inhibitor ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,030304 developmental biology ,Mice, Inbred BALB C ,0303 health sciences ,Nelfinavir ,Ritonavir ,Protease ,biology ,Adenine nucleotide translocator ,virus diseases ,HIV Protease Inhibitors ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Shock, Septic ,Molecular biology ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,3. Good health ,Mice, Inbred C57BL ,Stroke ,Disease Models, Animal ,Mitochondrial permeability transition pore ,biology.protein ,Female ,Mitochondrial ADP, ATP Translocases ,030217 neurology & neurosurgery ,Research Article ,Signal Transduction ,medicine.drug - 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.
- Published
- 2005