Abstract：
BACKGROUND: The roles of Caveolin-1 (Cav-1) and the Wnt/β-catenin signaling pathways in cerebral ischemia-reperfusion (I/R) injury are well established. The translocation of β-catenin into the nucleus is critical for regulating neuronal apoptosis, repair, and neurogenesis within the ischemic brain. It has been reported that the scaffold domain of Caveolin-1 (Cav-1) (residues 95-98) interacts with β-catenin (residues 330-337). However, the specific contribution of the Cav-1/β-catenin complex to I/R injury remains unknown.
RESULTS: To investigate the mechanism underlying the involvement of the Cav-1/β-catenin complex in the subcellular translocation of β-catenin and its subsequent effects on cerebral I/R injury, we treated ischemic brains with ASON (Cav-1 antisense oligodeoxynucleotides) or FTVT (a competitive peptide antagonist of the Cav-1 and β-catenin interaction). Our study demonstrated that the binding of Cav-1 to β-catenin following I/R injury prevented the nuclear accumulation of β-catenin. Treatment with ASON or FTVT after I/R injury significantly increased the levels of nuclear β-catenin. Furthermore, ASON reduced the phosphorylation of β-catenin at Ser33, Ser37, and Thr41, which contributes to its proteasomal degradation, while FTVT increased phosphorylation at Tyr333, which is associated with its nuclear translocation.
CONCLUSIONS: The above results indicate that the formation of the Cav-1/β-catenin complex anchors β-catenin in the cytoplasm following I/R injury. Additionally, both ASON and FTVT treatments attenuated neuronal death in ischemic brains. Our study suggests that targeting the interaction between Cav-1 and β-catenin serve as a novel therapeutic strategy to protect against neuronal damage during cerebral injury.
RESULTS: To investigate the mechanism underlying the involvement of the Cav-1/β-catenin complex in the subcellular translocation of β-catenin and its subsequent effects on cerebral I/R injury, we treated ischemic brains with ASON (Cav-1 antisense oligodeoxynucleotides) or FTVT (a competitive peptide antagonist of the Cav-1 and β-catenin interaction). Our study demonstrated that the binding of Cav-1 to β-catenin following I/R injury prevented the nuclear accumulation of β-catenin. Treatment with ASON or FTVT after I/R injury significantly increased the levels of nuclear β-catenin. Furthermore, ASON reduced the phosphorylation of β-catenin at Ser33, Ser37, and Thr41, which contributes to its proteasomal degradation, while FTVT increased phosphorylation at Tyr333, which is associated with its nuclear translocation.
CONCLUSIONS: The above results indicate that the formation of the Cav-1/β-catenin complex anchors β-catenin in the cytoplasm following I/R injury. Additionally, both ASON and FTVT treatments attenuated neuronal death in ischemic brains. Our study suggests that targeting the interaction between Cav-1 and β-catenin serve as a novel therapeutic strategy to protect against neuronal damage during cerebral injury.
摘要：
背景：小窝蛋白-1（Cav-1）和Wnt/β-catenin信号通路在脑缺血再灌注（I/R）损伤中的作用已得到证实。β-catenin易位到细胞核是调节神经元凋亡的关键,修复,和缺血脑内的神经发生。据报道,小窝蛋白-1(Cav-1)的支架结构域(残基95-98)与β-连环蛋白(残基330-337)相互作用。然而,Cav-1/β-catenin复合物对I/R损伤的具体作用尚不清楚。
结果：为了研究Cav-1/β-catenin复合物参与β-catenin亚细胞易位的机制及其对脑I/R损伤的后续影响，我们用ASON（Cav-1反义寡脱氧核苷酸）或FTVT（Cav-1和β-catenin相互作用的竞争性肽拮抗剂）治疗缺血性脑。我们的研究表明，I/R损伤后Cav-1与β-catenin的结合阻止了β-catenin的核积累。I/R损伤后用ASON或FTVT治疗可显着增加核β-连环蛋白的水平。此外，ASON降低了β-catenin在Ser33，Ser37和Thr41的磷酸化，这有助于其蛋白酶体降解，而FTVT在Tyr333处增加磷酸化，这与其核易位有关。
结论：上述结果表明，在I/R损伤后，Cav-1/β-catenin复合物的形成在细胞质中锚定了β-catenin。此外,ASON和FTVT治疗均减轻了缺血性脑中的神经元死亡。我们的研究表明，靶向Cav-1和β-catenin之间的相互作用可作为一种新型的治疗策略，以防止脑损伤期间的神经元损伤。
结果：为了研究Cav-1/β-catenin复合物参与β-catenin亚细胞易位的机制及其对脑I/R损伤的后续影响，我们用ASON（Cav-1反义寡脱氧核苷酸）或FTVT（Cav-1和β-catenin相互作用的竞争性肽拮抗剂）治疗缺血性脑。我们的研究表明，I/R损伤后Cav-1与β-catenin的结合阻止了β-catenin的核积累。I/R损伤后用ASON或FTVT治疗可显着增加核β-连环蛋白的水平。此外，ASON降低了β-catenin在Ser33，Ser37和Thr41的磷酸化，这有助于其蛋白酶体降解，而FTVT在Tyr333处增加磷酸化，这与其核易位有关。
结论：上述结果表明，在I/R损伤后，Cav-1/β-catenin复合物的形成在细胞质中锚定了β-catenin。此外,ASON和FTVT治疗均减轻了缺血性脑中的神经元死亡。我们的研究表明，靶向Cav-1和β-catenin之间的相互作用可作为一种新型的治疗策略，以防止脑损伤期间的神经元损伤。
