Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
Antioxid Redox Signal. 2023 Mar;38(7-9):496-528. doi: 10.1089/ars.2021.0263. Epub 2022 Nov 1.
KRIT1 (Krev interaction trapped 1) is a scaffolding protein that plays a critical role in vascular morphogenesis and homeostasis. Its loss-of-function has been unequivocally associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease of genetic origin characterized by defective endothelial cell-cell adhesion and ensuing structural alterations and hyperpermeability in brain capillaries. KRIT1 contributes to the maintenance of endothelial barrier function by stabilizing the integrity of adherens junctions and inhibiting the formation of actin stress fibers. Among the multiple regulatory mechanisms proposed so far, significant evidence accumulated over the past decade has clearly shown that the role of KRIT1 in the stability of endothelial barriers, including the blood-brain barrier, is largely based on its involvement in the complex machinery governing cellular redox homeostasis and responses to oxidative stress and inflammation. KRIT1 loss-of-function has, indeed, been demonstrated to cause an impairment of major redox-sensitive mechanisms involved in spatiotemporal regulation of cell adhesion and signaling, which ultimately leads to decreased cell-cell junction stability and enhanced sensitivity to oxidative stress and inflammation. This review explores the redox mechanisms that influence endothelial cell adhesion and barrier function, focusing on the role of KRIT1 in such mechanisms. We propose that this supports a novel model wherein redox signaling forms the common link between the various pathogenetic mechanisms and therapeutic approaches hitherto associated with CCM disease. A comprehensive characterization of the role of KRIT1 in redox control of endothelial barrier physiology and defense against oxy-inflammatory insults will provide valuable insights into the development of precision medicine strategies. 38, 496-528.
KRIT1（Krev 相互作用陷 1）是一种支架蛋白，在血管形态发生和稳态中起着关键作用。其功能丧失与脑动静脉畸形（CCM）的发病机制明确相关，CCM 是一种主要的遗传性脑血管疾病，其特征是内皮细胞-细胞黏附缺陷，并随后导致脑毛细血管的结构改变和通透性增加。KRIT1 通过稳定黏附连接的完整性并抑制肌动蛋白应力纤维的形成，有助于维持内皮屏障功能。到目前为止，已经提出了多种调节机制，过去十年积累的大量证据清楚地表明，KRIT1 在维持内皮屏障（包括血脑屏障）的稳定性中的作用主要基于其参与调节细胞氧化还原稳态以及对氧化应激和炎症反应的复杂机制。KRIT1 功能丧失确实导致涉及细胞黏附和信号时空调节的主要氧化还原敏感机制受损，最终导致细胞-细胞连接稳定性降低和对氧化应激和炎症的敏感性增强。本综述探讨了影响内皮细胞黏附和屏障功能的氧化还原机制，重点介绍了 KRIT1 在这些机制中的作用。我们提出，这支持了一种新的模型，其中氧化还原信号是各种发病机制和迄今为止与 CCM 疾病相关的治疗方法之间的共同联系。全面描述 KRIT1 在氧化还原控制内皮屏障生理学和抵御氧炎性损伤中的作用，将为开发精准医学策略提供有价值的见解。Cell 38, 496-528.
