The 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) is an E3 ubiquitin ligase that can preserve heart structure and function, but its role in endothelial dysfunction and atherosclerosis (AS) is unclear. The aim of this study was to explore the role and biological function of HRD1 in AS. HRD1 expression was significantly decreased in atherosclerotic intima and ox-LDL led to a decrease of HRD1 level in endothelial cells (ECs). Forced expression of HRD1 inhibited the endothelial apoptosis induced by ox-LDL. The transcription factor KLF2 specifically bound to the HRD1 promoter and positively regulated HRD1 expression. KLF2 up-regulation could reverse the decrease of HRD1 level in ECs treated with ox-LDL. Further analysis showed that HRD1 interacted with LOX-1 and promoted ubiquitination and degradation of LOX-1 by the proteasome. Deletion of LOX-1 attenuated the ECs apoptosis induced by HRD1 downregulation. Pravastatin, which protected EC from damage via a KLF2-dependent mechanism, could dose-dependently enhanced HRD1 expression in EC exposed to ox-LDL. Interestingly, interference of HRD1 abolished the cytoprotective effect of pravastatin. Collectively, our data indicate that decreased HRD1 expression leads to apoptosis of ECs and restoration of HRD1 expression could represent a novel strategy for human AS therapy.