BH4-domain peptide from Bcl-xL exerts anti-apoptotic activity in vivo.
The Bcl-2 family of proteins regulates apoptosis chiefly by controlling mitochondrial membrane permeability. It has previously been shown that the BH4 domain of Bcl-2/Bcl-xL is essential for the prevention of apoptotic mitochondrial changes, including the release of cytochrome c and apoptotic cell death. We have previously reported that BH4 peptide fused to the protein transduction domain of HIV-1 TAT protein (TAT-BH4) significantly inhibits etoposide-induced apoptosis in a cell line. This time, we investigated whether TAT-BH4 peptide was cytoprotective in ex vivo and in vivo rodent models. Intraperitoneal injection of TAT-BH4 peptide greatly inhibited X-ray-induced apoptosis in the small intestine of mice and partially suppressed Fas-induced fulminant hepatitis. In addition, this peptide markedly suppressed heart failure after ischemia-reperfusion injury in isolated rat heart, probably by preventing mitochondrial dysfunction. These findings demonstrate that TAT-BH4 peptide exerts anti-apoptotic activity both in vivo and ex vivo, and imply that it may be a useful therapeutic agent for diseases involving mitochondrial dysfunction and apoptosis.
Sugioka
Rie
R
Department of Post-Genomics & Diseases, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Shimizu
Shigeomi
S
Funatsu
Toshihiro
T
Tamagawa
Hiroshi
H
Sawa
Yoshiki
Y
Kawakami
Toru
T
Tsujimoto
Yoshihide
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D006367:HeLa Cells; D006505:Hepatitis / Q000188:drug therapy; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014965:X-Rays; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein