Selective involvement of BH3-only Bcl-2 family members Bim and Bad in neonatal hypoxia-ischemia.
Perinatal hypoxic-ischemic injury is a common cause of neurologic disability mediated in part by Bcl-2 family-regulated neuronal apoptosis. The Bcl-2 protein family consists of both pro- (e.g. Bax, Bad, Bid, Bim) and anti-apoptotic (e.g. Bcl-2, Bcl-X(L)) proteins that regulate mitochondrial outer membrane integrity, cytochrome c release and caspase activation. Previous studies have implicated Bax as an important mediator of neuronal death in several models of brain injury, including neonatal hypoxia-ischemia (HI). In this study, we assessed the roles of several members of the pro-apoptotic BH3 domain-only Bcl-2 sub-family in an in vivo mouse model of neonatal HI. Seven-day old control and gene-disrupted mice underwent unilateral left carotid ligation followed by 45 min exposure to 8% oxygen and the extent of brain injury was assessed 2 days later. Following HI, mice deficient in Bad or Bim exhibited reduced activated caspase-3 and glial fibrillary acidic protein immunostaining in their brains compared to similarly treated control animals. Measurement of hippocampal area showed decreased parenchymal loss in both Bad- and Bim-deficient mice versus control animals. In contrast, loss of Bid, another BH3-only protein, provided no protection from neonatal HI brain injury. These results indicate that Bad and Bim are selectively involved in neuron death following neonatal HI and may be targets for therapeutic intervention.
Ness
Jayne M
JM
Department of Pediatrics, University of Alabama at Birmingham, 35487, USA. jness@peds.uab.edu
Harvey
Cary A
CA
Strasser
Andreas
A
Bouillet
Philippe
P
Klocke
Barbara J
BJ
Roth
Kevin A
KA
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000293:injuries / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C494820:Bad protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases