An apolipoprotein E receptor mimetic peptide decreases blood-brain barrier permeability following intracerebral hemorrhage by inhibiting the CypA/MMP-9 signaling pathway via LRP1 activation

Review

作者: Wang, Likun ; Ren, Siyin ; Wang, Long ; Jun, Tan ; Hang, Hang ; Wang, Ningning ; Li, Chen ; Chen, Xing ; Wu, Guofeng

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.

2017-06-01·Translational Stroke Research2区 · 医学

Inhibition of Blood-Brain Barrier Disruption by an Apolipoprotein E-Mimetic Peptide Ameliorates Early Brain Injury in Experimental Subarachnoid Hemorrhage

2区 · 医学

Article

作者: Vitek, Michael P ; Pang, Jinwei ; Peng, Jianhua ; Sun, Xiaochuan ; Yang, Ping ; Kuai, Li ; Chen, Yitian ; Chen, Ligang ; Jiang, Yong ; Wu, Yue ; Chen, Yue

Apolipoprotein E (ApoE)-mimetic peptides have been demonstrated to be beneficial in secondary brain injury following experimental subarachnoid hemorrhage (SAH). However, the molecular mechanisms underlying these benefits in SAH models have not been clearly identified. This study investigated whether an ApoE-mimetic peptide affords neuroprotection in early brain injury (EBI) following SAH by attenuating BBB disruption. SAH was induced by an endovascular perforation in young, healthy, male wild-type (WT) C57BL/6J mice. Multiple techniques, including MRI with T2-weighted imaging, ¹⁸ FDG PET-CT scanning and histological studies, were used to examine BBB integrity and neurological dysfunction in EBI following SAH. We found that SAH induced a significant increase of BBB permeability and neuron apoptosis, whereas ApoE-mimetic peptide treatment significantly reduced the degradation of tight junction proteins and endothelial cell apoptosis. These effects reduced brain edema and neuron apoptosis, increased cerebral glucose uptake, and improved neurological functions. Further investigation revealed that the ApoE-mimetic peptide inhibited the proinflammatory activators of MMP-9, including CypA, NF-κB, IL-6, TNF-α, and IL-1β, thereby ameliorating BBB disruption at the acute stage of SAH. Together, these data indicate that ApoE-mimetic peptide may be a novel and promising therapeutic strategy for EBI amelioration after SAH that are worthy of further study.

2015-05-01·Transplantation2区 · 医学

Attenuation of Acute Rat Renal Allograft Rejection by Apolipoprotein E-Mimetic Peptide

2区 · 医学

Article

作者: Zakrzewicz, Anna ; Padberg, Winfried ; Lochnit, Guenter ; Reichert, Martin ; Grau, Veronika ; Kutlimuratov, Khusin ; Wilhelm, Jochen ; Atanasova, Srebrena ; Schmitz, Jessica ; Zakrzewicz, Dariusz

BACKGROUNDIn addition to its well-described role in lipid metabolism, apolipoprotein E (ApoE) exerts immunomodulatory functions. A protective role of ApoE and ApoE-mimetic peptide (ApoE(133-149)) application was documented in several inflammatory disorders. In this study, we test the hypothesis that ApoE(133-149) promotes renal allograft survival.METHODSDark Agouti, Brown Norway, and Fischer 344 kidneys were transplanted to Lewis rats to investigate fatal and reversible acute rejection. Apolipoprotein E expression was assessed in intravascular leukocytes of renal grafts, in graft tissue and in recipient blood plasma. Recipients of Brown Norway kidneys were treated with ApoE(133-149), and graft survival was monitored until day 100. Graft infiltration, cytokine, and chemokine production were analyzed.RESULTSIntravascular graft leukocytes and renal tissue obtained from animals undergoing reversible acute rejection expressed increased levels of ApoE mRNA, whereas during fatal rejection, ApoE expression was reduced or remained unchanged. Animals treated with ApoE(133-149) showed prolonged allograft survival, which was associated with a reduced infiltration of CD8 and α/β T-cell receptor-expressing cells, diminished Granzyme B mRNA expression, and decreased caspase-3 activation.CONCLUSIONSEndogenous ApoE overexpression and exogenous application of ApoE(133-149) seem to protect renal allografts from fatal acute rejection. This effect was associated with a reduced influx of cytotoxic T cells.

100 项与 AEM-18 相关的药物交易

登录后查看更多信息