Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC, USA.
Stroke. 2012 Feb;43(2):571-4. doi: 10.1161/STROKEAHA.111.625467. Epub 2011 Oct 27.
Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal-dominant) forms with mutations in 1 of 3 gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell-cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase. Although Rho kinase inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo.
Our recently generated a model of CCM1 disease (Ccm1(+/-)Msh2(-/-)) was treated with the Rho kinase inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals' brains. For comparison, we also assessed therapeutic effect in previously described Ccm2(+/-)Trp53(-/-) mice treated with the same dose and duration of fasudil and placebo.
Fasudil-treated Ccm1(+/-)Msh2(-/-) mice had a significantly decreased prevalence of CCM lesions compared with placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation, and endothelial proliferation and exhibited decreased expression of Rho kinase activation biomarkers. A therapeutic effect was also documented in Ccm2(+/-)Trp53(-/-) mice.
This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs and indicates that Rho kinase activation is a critical step in CCM lesion genesis and maturation.
脑海绵状血管畸形（CCMs）的特征是毛细血管明显扩张，伴有血管渗漏和出血，并以散发或遗传（常染色体显性）形式发生，突变位于 3 个基因座中的 1 个（CCM1、2 或 3）。我们之前报道过 CCM1 蛋白（KRIT1）定位于内皮细胞-细胞连接处，KRIT1 的缺失导致连接不稳定，与 RhoA 及其效应物 Rho 激酶的激活有关。尽管 Rho 激酶抑制已被提议作为 CCM 的潜在治疗方法，但尚未在体内证明对 CCM 病变发生有治疗作用。
我们最近生成了一种 CCM1 疾病模型（Ccm1(+/-)Msh2(-/-)），用 Rho 激酶抑制剂法舒地尔（100mg/kg/天，从断奶到 5 个月龄通过饮用水给予）或安慰剂处理，并通过对动物大脑进行系统检查来盲法评估 CCM 病变负担。为了比较，我们还评估了以前描述的 Ccm2(+/-)Trp53(-/-)小鼠用相同剂量和时间的法舒地尔和安慰剂治疗的治疗效果。
与安慰剂对照组相比，法舒地尔治疗的 Ccm1(+/-)Msh2(-/-)小鼠 CCM 病变的发生率显著降低。治疗动物的病变较小，出血、炎症和内皮细胞增殖的可能性较小，并且 Rho 激酶激活生物标志物的表达降低。在 Ccm2(+/-)Trp53(-/-)小鼠中也观察到了治疗效果。
这是首次报道 Rho 激酶激活在 CCM 病变发生和成熟中的关键作用，表明药物治疗在 CCM 的发展和进展中具有治疗益处。
