Chen Xing, Wang Long, Wang Ningning, Li Chen, Hang Hang, Wu Guofeng, Ren Siyin, Jun Tan, Wang Likun
The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, PR China; Guizhou Medical University, Guiyang 550004, Guizhou Province, PR China.
The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, PR China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 3):113007. doi: 10.1016/j.intimp.2024.113007. Epub 2024 Oct 31.
Apolipoprotein (Apo) E mimetic peptides down-regulate the inflammatory response and alleviate damage to secondary neurons after intracerebral hemorrhage (ICH). We designed a novel apoE receptor mimetic composed of the low-density lipoprotein receptor-associated protein-1 (LRP1) receptor-binding domain of apoE with 6 lysines (6KApoEp). The 6KApoEp peptide is small enough to penetrate the blood-brain barrier (BBB) and modulate the inflammatory response during damage to the central nervous system. LRP1 inhibits the CypA/MMP-9 pathway and reduces BBB damage. Thus, we examined the effects of 6KApoEp-LRP1 interaction. LRP1 and 6KApoEp interacted and co-localized in the pericytes. We established a Sprague-Dawley (SD) male rat model of ICH to observe the role of 6KApoEp in secondary injury after ICH. The expression levels of cyclophilin A (CypA), nuclear factor kappa-B (NF-κB) p65, and matrix metalloproteinase 9 (MMP-9) were increased, the expression levels of ZO-1, claudin-5, and occludin were decreased, and brain water content and BBB permeability increased in the ICH model. The expression of CypA, NF-κB, and MMP-9 decreased significantly around the hematoma, while the expression of tight junction-related proteins increased significantly in response to 6KApoEp, especially at the 100 μg/kg dose. LRP expression increased around the ICH focus in response to 6KApoEp treatment, thus increasing the influence on the expression of CypA, NF-κB, and MMP-9. We conclude that 6KApoEp inhibits the CypA/NF-κB/MMP-9 pathway by activating LRP1, resulting in reduced BBB damage and less brain edema around the ICH. These results provide the theoretical basis for improving the prognosis and treatment of ICH. Our results suggest that 6KApoEp activates LRP1, resulting in the attenuation of tight junction protein degradation (ZO-1, occludin, and claudin-5) via the CypA/NF-κB/MMP-9 signaling pathway. The increased tight junction protein levels improve the BBB and attenuate edema development in brain tissue around the hematoma following ICH.
载脂蛋白（Apo）E模拟肽可下调脑出血（ICH）后的炎症反应，并减轻对继发性神经元的损伤。我们设计了一种新型的载脂蛋白E受体模拟物，它由载脂蛋白E的低密度脂蛋白受体相关蛋白-1（LRP1）受体结合结构域与6个赖氨酸组成（6KApoEp）。6KApoEp肽足够小，能够穿透血脑屏障（BBB）并在中枢神经系统损伤期间调节炎症反应。LRP1可抑制环孢素A（CypA）/基质金属蛋白酶-9（MMP-9）途径，并减少血脑屏障损伤。因此，我们研究了6KApoEp与LRP1相互作用的影响。LRP1与6KApoEp在周细胞中相互作用并共定位。我们建立了Sprague-Dawley（SD）雄性大鼠脑出血模型，以观察6KApoEp在脑出血后继发性损伤中的作用。在ICH模型中，亲环素A（CypA）、核因子κB（NF-κB）p65和基质金属蛋白酶9（MMP-9）的表达水平升高，闭锁小带蛋白-1（ZO-1）、闭合蛋白-5（claudin-5）和咬合蛋白（occludin）的表达水平降低，脑含水量和血脑屏障通透性增加。在血肿周围，CypA、NF-κB和MMP-9的表达显著降低，而紧密连接相关蛋白的表达在给予6KApoEp后显著增加，尤其是在剂量为100μg/kg时。给予6KApoEp治疗后，ICH病灶周围的LRP表达增加，从而增加了对CypA、NF-κB和MMP-9表达的影响。我们得出结论，6KApoEp通过激活LRP1抑制CypA/NF-κB/MMP-9途径，从而减少血脑屏障损伤和ICH周围的脑水肿。这些结果为改善脑出血的预后和治疗提供了理论依据。我们的结果表明，6KApoEp激活LRP1，通过CypA/NF-κB/MMP-9信号通路导致紧密连接蛋白降解（ZO-1、occludin和claudin-5）减弱。紧密连接蛋白水平的增加改善了血脑屏障，并减轻了脑出血后血肿周围脑组织的水肿发展。
