Disintegration of Cav-1/β-catenin complex attenuates neuronal death after ischemia-reperfusion injury by promoting β-catenin nuclear translocation.

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.

Methods And 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.