Caveolin-1 Deletion Reduces Early Brain Injury after Experimental Intracerebral Hemorrhage
Caveolin-1 Deletion Reduces Early Brain Injury after Experimental Intracerebral Hemorrhage
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DOI：
10.1016/j.ajpath.2010.12.023
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发表时间：
2011-04-01
影响因子：
6
通讯作者：
Shyue, Song-Kun
中科院分区：
文献类型：
--
作者：
Chang, Che-Feng;Chen, Shu-Fen;Shyue, Song-Kun
脑出血（ICH）是中风的一种亚型，发病率和死亡率很高。 Caveolin-1 (Cav-1) 是小窝的主要结构蛋白，参与调节细胞内的信号转导和胆固醇运输。尽管最近的一项研究表明 Cav-1 在脑缺血中具有保护作用，但其在 ICH 中的功能仍不清楚。在这项研究中，我们研究了 Cav-1 在胶原酶诱导的 ICH 模型和神经元培养物中的作用。我们的结果表明，Cav-1 在血肿周围区域（主要是内皮细胞）上调。与野生型小鼠相比，Cav-1 敲除小鼠在 ICH 后 1 天的损伤体积更小、神经功能缺损更轻、脑水肿和神经元死亡更少。 Cav-1敲除小鼠的保护机制与白细胞浸润显着减少、炎症介质表达减少（包括巨噬细胞炎症蛋白（MIP）-2和环氧合酶（COX）-2）以及基质金属蛋白酶-9活性降低有关。 Cav-1 的缺失还抑制了血红素加氧酶-1 的表达并减弱了 ICH 后活性氧的产生。此外，Cav-1 的缺失或敲低降低了神经元对血红素诱导的毒性的脆弱性，并减少了体外血红素加氧酶 (HO)-1 的诱导。这些数据表明 Cav-1 在 ICH 后的早期脑损伤中发挥有害作用。抑制Cav-1可能为治疗出血性中风提供新的治疗方法。 （Am J Pathol 2011，178：1749-1761；DOI：10.1016/j.ajpath.2010.12.023）
Intracerebral hemorrhage (ICH) is a subtype of stroke with high rates of morbidity and mortality. Caveolin-1 (Cav-1) is the main structural protein of caveolae and is involved in regulating signal transduction and cholesterol trafficking in cells. Although a recent study suggests a protective role of Cav-1 in cerebral ischemia, its function in ICH remains unknown. In this study, we examined the role of Cav-1 and in a model of collagenase-induced ICH and in neuronal cultures. Our results indicate that Cav-1 was up-regulated in the perihematomal area predominantly in endothelial cells. Cav-1 knockout mice had smaller injury volumes, milder neurologic deficits, less brain edema, and neuronal death 1 day after ICH than wild-type mice. The protective mechanism in Cav-1 knockout mice was associated with marked reduction in leukocyte infiltration, decreased expression of inflammatory mediators, including macrophage inflammatory protein (MIP)-2 and cyclooxygenase (COX)-2, and reduced matrix metalloproteinase-9 activity. Deletion of Cav-1 also suppressed heme oxygenase-1 expression and attenuated reactive oxygen species production after ICH. Moreover, deletion or knockdown of Cav-1 decreased neuronal vulnerability to hemin-induced toxicity and reduced heme oxygenase (HO)-1 induction in vitro. These data suggest that Cav-1 plays a deleterious role in early brain injury after ICH. Inhibition of Cav-1 may provide a novel therapeutic approach for the treatment of hemorrhagic stroke. (Am J Pathol 2011, 178:1749-1761; DOI: 10.1016/j.ajpath.2010.12.023)