miR-21/PTEN pathway mediates the cardioprotection of geniposide against oxidized low-density lipoprotein-induced endothelial injury via suppressing oxidative stress and inflammatory response

Oxidized low-density lipoprotein (ox-LDL)-induced vascular endothelial damage, oxidative stress and inflammation play a vital role in the pathophysiology of atherosclerosis. Geniposide is the primary active ingredient from Gardenia jasminoides Ellis associated with anti-oxidative properties and cardioprotective action. However, the therapeutic mechanism of geniposide in atherosclerosis remains unclear. Hence, the present study aimed to elucidate the underlying mechanisms of geniposide in oxidative stress and inflammatory response during ox-LDL injury in human umbilical vein endothelial cells (HUVECs), focusing particularly on the microRNA (miR)-21/PTEN pathway. The results demonstrated that geniposide pretreatment significantly increased cell viability, decreased lactate dehydrogenase release, increased miR-21 level and decreased PTEN expression under ox-LDL condition. Subsequently, transfection with miR-21 mimic enhanced the protection of geniposide on ox-LDL-induced cytotoxicity and apoptosis (mediated by the upregulation of apoptotic rate and caspase-3 activity), whereas miR-21 inhibitor reversed these effects of geniposide. In addition, geniposide resulted in an anti-oxidant effect as evidenced by the decrease in reactive oxygen species generation, malondialdehyde content and NADPH oxidase 2 expression, and the increase in superoxide dismutase, glutathione peroxidase and catalase activities in ox-LDL-treated HUVECs, which were exacerbated by miR-21 mimic and reversed by miR-21 inhibitor. Furthermore, geniposide mitigated the ox-LDL-induced inflammatory response, demonstrated by a downregulation of pro-inflammatory cytokine (IL-1β, IL-6, and TNF-α) levels and an upregulation of anti-inflammatory cytokine (IL-10) level. However, miR-21 mimic enhanced, whereas miR-21 inhibitor attenuated, these effects of geniposide. In conclusion, the present results indicated that geniposide protects HUVECs from ox-LDL injury by inhibiting oxidative stress and inflammation, and that these effects are partly due to the enhancement of the miR-21/PTEN pathway.