Neuroprotection mediated by changes in the endothelial actin cytoskeleton
Neuroprotection mediated by changes in the endothelial actin cytoskeleton
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DOI：
10.1172/jci9639
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发表时间：
2000-07-01
影响因子：
15.9
通讯作者：
Liao, JK
中科院分区：
文献类型：
--
作者：
Laufs, U;Endres, M;Liao, JK
脑血流量受内皮源性一氧化氮（NO）调节，内皮型一氧化氮合酶缺陷（eNOS缺陷; eNOS（-/-））小鼠在大脑中动脉（MCA）闭塞后发生较大的脑梗死。我们报告，Rho介导的内皮肌动蛋白细胞骨架的破坏导致eNOS表达上调，并降低大脑中动脉闭塞后脑缺血的严重程度。用Rho抑制剂肉毒梭菌C3转移酶（10 μ g/d）或肌动蛋白细胞骨架破坏剂细胞松弛素D（1 mg/kg）治疗的小鼠显示血管eNOS表达和活性增加2 - 4倍。这种eNOS表达的增加不是由于eNOS基因转录的增加，而是由于eNOS mRNA半衰期从10 +/- 3小时延长到24 +/- 4小时。事实上，过度表达显性负性Rho突变体（N19 RhoA）的内皮细胞表现出肌动蛋白应力纤维形成减少和eNOS表达增加。通过3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂辛伐他汀抑制血管Rho guano sine-5 '-triphosphate结合活性，增加了脑缺血区域的脑血流量，并且用辛伐他汀、C3转移酶或细胞松弛素D治疗的小鼠在MCA闭塞后显示出较小的脑梗死。在eNOS（-/-）小鼠中未观察到这些药物的神经保护作用。这些发现表明，靶向内皮肌动蛋白细胞骨架的治疗可能对缺血性卒中有有益的影响。
Cerebral blood flow is regulated by endothelium-derived nitric oxide (NO), and endothelial NO synthase-deficient (eNOS-deficient; eNOS(-/-)) mice develop larger cerebral infarctions following middle cerebral artery (MCA) occlusion. We report that disruption of Rho-mediated endothelial actin cytoskeleton leads to the upregulation of eNOS expression and reduces the severity of cerebral ischemia following MCA occlusion. Mice treated with the Rho inhibitor Clostridium botulinum C3 transferase (10 mu g/d) or the actin cytoskeleton disrupter cytochalasin D (1 mg/kg) showed a two- to fourfold increase in vascular eNOS expression and activity. This increase in eNOS expression was not due to increases in eNOS gene transcription, but to prolongation of eNOS mRNA half-life from 10 +/- 3 hours to 24 +/- 4 hours. Indeed, endothelial cells overexpressing a dominant-negative Rho mutant (N19RhoA) exhibited decreased actin stress fiber formation and increased eNOS expression. Inhibition of vascular Rho guano sine-5'-triphosphate binding activity by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin increased cerebral blood flow to ischemic regions of the brain, and mice treated with simvastatin, C3 transferase, or cytochalasin D showed smaller cerebral infarctions following MCA occlusion. No neuroprotection was observed with these agents in eNOS(-/-) mice. These findings suggest that therapies which target the endothelial actin cytoskeleton may have beneficial effects in ischemic stroke.