Inhibition of rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection
Inhibition of rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection
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DOI：
10.1161/01.str.0000181077.84981.11
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发表时间：
2005-10-01
期刊：
影响因子：
8.3
通讯作者：
Liao, JK
中科院分区：
文献类型：
--
作者：
Rikitake, Y;Kim, HH;Liao, JK
背景和目的-内皮源性一氧化氮（NO）在血管保护中起关键作用。Rho激酶（ROCK）抑制剂羟基法舒地尔（hydroxyfasudil）防止缺氧条件下内皮NO合酶（eNOS）的下调。然而，目前尚不清楚抑制ROCK是否可以减轻体内缺血诱导的内皮功能障碍和组织损伤。方法-用浓度不断增加的羟基法舒地尔（0.1至100 μ mol/ L）处理人血管内皮细胞，并测量eNOS表达和活性。为了确定ROCK对eNOS调节的生理相关性，我们给小鼠施用法舒地尔，法舒地尔在体内代谢为羟基法舒地尔，给药2天，然后使小鼠大脑中动脉闭塞。脑血流量，脑梗死面积，和神经功能缺损measured.Results -在浓度依赖性的方式，羟基法舒地尔增加eNOS mRNA和蛋白质的表达，导致在10 μ mol/ L的1.9和1.6倍的增加，分别（P < 0.05）。这与eNOS活性和NO产生分别增加1.5倍和2.3倍相关（两者P < 0.05）。法舒地尔增加缺血区和非缺血区的脑血流量，脑梗死面积减少33%，神经功能缺损评分改善37%（P < 0.05）。这与脑和血管ROCK活性的抑制以及eNOS表达和活性的增加相关。另一种ROCK抑制剂Y-27632也表现出类似的作用。法舒地尔的神经保护作用是不存在的eNOS缺陷mice.Conclusions -这些研究结果表明，ROCK抑制的神经保护作用是由内皮源性NO介导的，并表明ROCK可能是缺血性中风的一个重要的治疗靶点。
Background and Purpose - Endothelium-derived nitric oxide (NO) plays a pivotal role in vascular protection. The Rho kinase (ROCK) inhibitor, hydroxyfasudil, prevents the downregulation of endothelial NO synthase (eNOS) under hypoxic conditions. However, it is unknown whether inhibition of ROCK can attenuate ischemia- induced endothelial dysfunction and tissue damage in vivo.Methods - Human vascular endothelial cells were treated with increasing concentrations of hydroxyfasudil (0.1 to 100 mu mol/ L) and eNOS expression and activity were measured. To determine the physiological relevance of eNOS regulation by ROCK, we administered fasudil, which is metabolized to hydroxyfasudil in vivo, to mice for 2 days before subjecting them to middle cerebral artery occlusion. Cerebral blood flow, cerebral infarct size, and neurologic deficit were measured.Results - In a concentration-dependent manner, hydroxyfasudil increased eNOS mRNA and protein expression, resulting in a 1.9- and 1.6- fold increase, respectively, at 10 mu mol/ L (P < 0.05 for both). This correlated with a 1.5- and 2.3- fold increase in eNOS activity and NO production, respectively (P < 0.05 for both). Fasudil increased cerebral blood flow to both ischemic and nonischemic brain areas, reduced cerebral infarct size by 33%, and improved neurologic deficit score by 37% (P < 0.05). This correlated with inhibition of brain and vascular ROCK activity and increased eNOS expression and activity. Another ROCK inhibitor, Y-27632, also showed similar effects. The neuroprotective effects of fasudil were absent in eNOS-deficient mice.Conclusions - These findings indicate that the neuroprotective effect of ROCK inhibition is mediated by endothelium-derived NO and suggest that ROCK may be an important therapeutic target for ischemic stroke.