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

Abstract

Abstract The roles of Caveolin-1 (Cav-1) and Wnt/β-catenin signaling pathways in cerebral ischemia-reperfusion (I/R) injury are well established. Translocation of β-catenin into the nucleus is critical in regulating the apoptosis, repair, and nerve regeneration of neurons in the ischemic brain. Caveolin (Cav)-1 scaffold domain (residues 95-98) has been reported to interact with β-catenin (residues 330-337). However, the contribution of the Cav-1/β-catenin complex to I/R injury is currently unknown. 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 interaction Cav-1 and β-catenin). Our study showed that the binding of Cav-1 to β-catenin after I/R injury prevented the nuclear accumulation of β-catenin. The disruption of the Cav-1/β-catenin complex with ASON or FTVT after I/R injury significantly increased nuclear β-catenin. ASON and FTVT reduced the Ser33, Ser37 Thr41 phosphorylation of β-catenin, contributing to its proteasomal degradation; however, it increased the Tyr333 phosphorylation relating to its nuclear translocation. The above results indicated that the formation of the Cav-1/ β-catenin complex anchored the cytoplasmic β-catenin after I/R injury. Besides, both ASON and FTVT could attenuate neuronal death in ischemic brains. Our study suggests that targeting the interaction of Cav-1 with β-catenin could be a novel therapeutic strategy to protect against neuronal damage during cerebral injury.