Zhou Changman, Yamaguchi Mitsuo, Colohan Austin R T, Zhang John H
Department of Neurosurgery, Louisiana State University Health Sciences Center--Shreveport, Shreveport, Louisiana, USA.
J Cereb Blood Flow Metab. 2005 May;25(5):572-82. doi: 10.1038/sj.jcbfm.9600069.
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.
我们之前的研究表明，大脑主要动脉内皮细胞的凋亡会导致蛛网膜下腔出血（SAH）后的脑血管痉挛。本研究使用已建立的犬双次出血模型，研究肿瘤抑制因子p-53在脑血管痉挛中的病理作用。将20只杂种犬分为四组：（1）对照组，（2）SAH组，（3）SAH+二甲基亚砜（溶剂）组，（4）SAH+匹非司亭-α（PFT）（p53抑制剂）组。从第0天到第3天，每天向枕大池注射p53抑制剂（200 nmol/L）。在第0天和第7天进行血管造影。对SAH后第7天收集的基底动脉进行蛋白质免疫印迹、细胞增殖测定、组织学检查和TUNEL染色。SAH组、SAH+二甲基亚砜组和SAH+PFT组在第7天的动脉直径分别为42%±4%、40%±5%和59%±4%。此外，在第7天观察到基底动脉TUNEL阳性染色以及p53、Bax和增殖细胞核抗原（PCNA）的蛋白表达增加。PFT抑制内皮细胞凋亡和平滑肌细胞增殖，并减轻血管造影显示的血管痉挛。总之，p53可能是SAH后内皮细胞凋亡和平滑肌细胞增殖的关键因素。抑制p53可能潜在地减少甚至预防脑血管痉挛。
