Protective effect of sonic hedgehog against oxidized low-density lipoprotein-induced endothelial apoptosis: Involvement of NF-κB and Bcl-2 signaling

Sonic hedgehog (Shh) is pivotally important in embryonic and adult blood vessel development and homeostasis. However, whether Shh is involved in atherosclerosis and plays a role in endothelial apoptosis induced by oxidized low-density lipoprotein (ox-LDL) has not been reported. The present study used recombinant Shh-N protein (rShh-N) and a plasmid encoding the human Shh gene (phShh) to investigate the role of Shh in ox-LDL-mediated human umbilical vein endothelial cell (HUVEC) apoptosis. The present study found that ox-LDL was able to induce apoptosis in HUVECs and that Shh protein expression was downregulated. Furthermore, pretreatment with rShh-N or transfection with phShh increased anti-apoptosis protein Bcl-2 expression and decreased cell apoptosis. These protective effects of rShh-N could be abolished by cyclopamine, which is a hedgehog signaling inhibitor. Furthermore, a co-immunoprecipitation assay was performed to demonstrate that Shh interacted with NF-κB p65 in HUVECs. Additionally, ox-LDL upregulated the phosphorylation of NF-κB p65 and inhibitor of NF-κB-α (IκBα), and these effects decreased notably following rShh-N and phShh treatment. Together, the present findings suggested that Shh serves an important protective role in alleviating ox-LDL-mediated endothelial apoptosis by inhibiting the NF-κB signaling pathway phosphorylation and Bcl-2 mediated mitochondrial signaling.