In vivo PDGF beta receptor activation in the dorsocaudal brainstem of the rat prevents hypoxia-induced apoptosis via activation of Akt and BAD.
Activation of platelet-derived growth factor receptor beta (PDGFR) within the caudal brainstem modulates the hypoxic ventilatory response. Since hypoxia does not induce apoptosis in the caudal brainstem, PDGFR could underlie such protective mechanism via a PI3 kinase-dependent phosphorylation of both Akt and BAD pathways. To further study this issue, caudal brainstem lysates were harvested from Sprague--Dawley rats during hypoxia (10% O(2)) after treatment with either vehicle or CGP 57148B (100 mg/kg), a selective blood-brain barrier-permeable PDGFR antagonist. Time-dependent increases in phosphorylated Akt occurred during hypoxia, peaking at 45' and lasting for up to 6 h, without parallel changes in total Akt protein. CGP 57148B attenuated Akt activation at all time points. Similarly, phosphorylation of BAD at serine136 but not at serine 112 occurred in the caudal brainstem as early as 15' of hypoxia, and was completely blocked by CGP 57148B. Furthermore, CGP 57148B treatment elicited significant increases in single-stranded DNA, caspase-like activity, and cleaved caspase 3 after 24 h of hypoxia that were absent in the caudal brainstem of hypoxic vehicle-treated animals. We conclude that PDGFR-dependent in vivo activation of both Akt and BAD during hypoxia prevents induction of apoptosis, and may contribute to the increased hypoxic tolerance of brainstem neurons.
Constance S. Kaufman Pediatric Pulmonary Research Laboratory, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA.
N
N
Simakajornboon
N J
NJ
Szerlip
E
E
Gozal
J W
JW
Anonetapipat
D
D
Gozal
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004277:DNA, Single-Stranded / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects* / Q000378:metabolism; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017552:Solitary Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051025:bcl-Associated Death Protein
C494821:Bad protein, rat; D001549:Benzamides; D002352:Carrier Proteins; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D051025:bcl-Associated Death Protein; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases