Role of p53 and apoptosis in cerebral vasospasm after experimental subarachnoid hemorrhage.
Our previous studies indicate that apoptosis in endothelial cells of major cerebral arteries contributes to cerebral vasospasm after subarachnoid hemorrhage (SAH). This study examined the pathologic roles of tumor suppressor p-53 in cerebral vasospasm using an established dog double-hemorrhage model. Twenty mongrel dogs were divided into four groups: (1) control, (2) SAH, (3) SAH+DMSO (vehicle), and (4) SAH+pifithrin-alpha (PFT) (p53 inhibitor). The p53 inhibitor (200 nmol/L) was injected into the cisterna magna daily from Day 0 through Day 3. Angiogram was performed on Day 0 and Day 7. Western blot, cell proliferation assay, histology, and TUNEL staining were conducted on the basilar arteries collected on Day 7 after SAH. The arterial diameter on Day 7 was 42%+/-4%, 40%+/-5%, and 59%+/-4% for SAH, SAH+DMSO, and SAH+PFT, respectively. In addition, positive staining of TUNEL and increased protein expression of p53, Bax, and PCNA in the basilar artery were observed on Day 7. PFT suppressed apoptosis in endothelial cells and proliferation in smooth muscle cells, and attenuated angiographic vasospasm. In conclusion, p53 may be a key factor in endothelial apoptosis and smooth muscle proliferation after SAH. Inhibition of p53 may potentially reduce or even prevent cerebral vasospasm.
Zhou
Changman
C
Department of Neurosurgery, Louisiana State University Health Sciences Center--Shreveport, Shreveport, Louisiana, USA.
Yamaguchi
Mitsuo
M
Colohan
Austin R T
AR
Zhang
John H
JH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052160:Benzothiazoles; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002533:Cerebral Angiography; D004195:Disease Models, Animal; D004285:Dogs; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D013844:Thiazoles / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*
D052160:Benzothiazoles; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin