Role of Rho-Associated Kinase in the Pathophysiology of Cerebral Cavernous Malformations.
Role of Rho-Associated Kinase in the Pathophysiology of Cerebral Cavernous Malformations.
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DOI：
10.1212/nxg.0000000000200121
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发表时间：
2024-02
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影响因子：
--
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中科院分区：
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脑海绵状血管瘤是一种以多孔内皮为特征的血管性病变。缺乏足够的内皮屏障可导致微出血和直接脑出血。病变发展的主要机制是3个CCM基因（CCM1、CCM2和CCM3）中至少1个基因的序列变异，这些基因影响导致CCM表型的各种信号通路。与CCM基因功能丧失相关的一个常见下游过程涉及RhoA及其效应物RhoA相关激酶（ROCK）的过度激活。在这项研究中，我们回顾了RhoA/ rock相关机制参与CCM病理生理作为潜在的治疗靶点。在PubMed中使用与RhoA/ROCK和ccm相关的搜索词组合进行文献检索。在内皮细胞中，CCM1、CCM2和CCM3蛋白通常结合形成CCM蛋白复合物，其调节多种蛋白靶点（如MAP3K3、SMURF1、SOK-1和ICAP-1）的功能，直接或间接增加RhoA/ROCK活性。CCM复合物功能的丧失和RhoA/ROCK活性的增加可导致应力纤维的形成，从而导致内皮连接不稳定。RhoA/ rock介导的其他病理生理结果包括向衰老相关分泌表型的转变（主要由ROCK2介导），其特征是内皮细胞迁移、细胞周期阻滞、细胞外基质降解、白细胞趋化和炎症。ROCK是一种潜在的治疗靶点，在临床前CCM模型中，直接（法舒地尔，NRL-1049）和间接（他汀类）ROCK抑制剂已显示出不同程度的减轻病变负担的疗效。目前的（阿托伐他汀）和计划中的（NRL-1049）临床研究将确定ROCK抑制剂对人类CCM的疗效，目前还没有美国食品和药物管理局批准或欧盟批准的药物治疗方法。
Cerebral cavernous malformations (CCMs) are vascular lesions characterized by a porous endothelium. The lack of a sufficient endothelial barrier can result in microbleeds and frank intracerebral hemorrhage. A primary mechanism for lesion development is a sequence variant in at least 1 of the 3 CCM genes (CCM1, CCM2, and CCM3), which influence various signaling pathways that lead to the CCM phenotype. A common downstream process associated with CCM gene loss of function involves overactivation of RhoA and its effector Rho-associated kinase (ROCK). In this study, we review RhoA/ROCK–related mechanisms involved in CCM pathophysiology as potential therapeutic targets. Literature searches were conducted in PubMed using combinations of search terms related to RhoA/ROCK and CCMs. In endothelial cells, CCM1, CCM2, and CCM3 proteins normally associate to form the CCM protein complex, which regulates the functions of a wide variety of protein targets (e.g., MAP3K3, SMURF1, SOK-1, and ICAP-1) that directly or indirectly increase RhoA/ROCK activity. Loss of CCM complex function and increased RhoA/ROCK activity can lead to the formation of stress fibers that contribute to endothelial junction instability. Other RhoA/ROCK–mediated pathophysiologic outcomes include a shift to a senescence-associated secretory phenotype (primarily mediated by ROCK2), which is characterized by endothelial cell migration, cell cycle arrest, extracellular matrix degradation, leukocyte chemotaxis, and inflammation. ROCK represents a potential therapeutic target, and direct (fasudil, NRL-1049) and indirect (statins) ROCK inhibitors have demonstrated various levels of efficacy in reducing lesion burden in preclinical models of CCM. Current (atorvastatin) and planned (NRL-1049) clinical studies will determine the efficacy of ROCK inhibitors for CCM in humans, for which no US Food and Drug Administration–approved or EU-approved pharmacologic treatment exists.
影响因子：
3.6
作者：
Joshi C
通讯作者：
Joshi C
影响因子：
3.7
作者：
Richardson BT;Dibble CF;Borikova AL;Johnson GL
通讯作者：
Johnson GL
影响因子：
3.5
作者：
Fisher OS;Zhang R;Li X;Murphy JW;Demeler B;Boggon TJ
通讯作者：
Boggon TJ