The vascular complications in heart, brain, kidney and retina are the most common chronic complications of diabetes mellitus (DM). At present, it has become a research hotspot to regulate the abnormal apoptosis of vascular endothelial cells for DM treatment. UNC0321 is a high affinity GPCRs inhibitor, and has potential practical value in chromatin remodeling. In this study, we treated HUVEC with UNC0321 in vitro, and found that UNC0321 inhibit the level of Cleaved-Caspase3 and Bax, thus inhibiting the apoptosis caused by high glucose. In addition, UNC0321 also promoted cell proliferation and migration by activating Akt / mTOR pathway. The transcriptome changes of HUVEC cells cultured with high glucose with or without the treatment of UNC0321 were analysis using sequencing. It was found that Rab4 expression was significantly inhibited after UNC0321 treatment. Subsequently, we overexpressed Rab4 in HUVEC cells cultured with high glucose, and found that overexpression of Rab4 promoted the apoptosis, and inhibited cell proliferation and migration. At the same time, after overexpression of Rab4 in HUVEC cells treated with UNC0321, the number of apoptosis was significantly increased, cell proliferation and migration were inhibited, and the activity of Akt / mTOR pathway decreased. These data suggested that overexpression of Rab4 effectively blocked the inhibition of apoptosis and the increase of cell proliferation induced by UNC0321. In conclusion, we found that UNC0321 inhibits the apoptosis of HUVEC cells caused by high glucose through inhibiting Rab4 expression, providing new potential drugs and targets for the treatment of diabetic vascular complications.