Astaxanthin Inhibits ox‐LDL‐Induced Early Endothelial Progenitor Cells Oxidative Stress and Apoptosis Through Nrf2 Activation

Astaxanthin exerts potent protective effects against stem cell apoptosis. This study investigated the protective efficacy of astaxanthin against oxidized low‐density lipoprotein (ox‐LDL)‐induced oxidative stress and apoptosis in endothelial progenitor cells (EPCs). Human early EPCs cultured in vitro were challenged with ox‐LDL in the presence or absence of astaxanthin. Results showed that ox‐LDL exposure significantly reduced nuclear factor‐E2‐related factor 2 (Nrf2) nuclear translocation in EPCs, while increasing oxidative stress and apoptosis rates. Astaxanthin pretreatment attenuated ox‐LDL‐induced reactive oxygen species (ROS) generation and EPC apoptosis, preserved mitochondrial membrane potential (MMP), and concomitantly enhanced nuclear Nrf2 accumulation while upregulating NQO1, HO‐1, and glutathione (GSH) levels. Nrf2 small interfering RNA (siRNA)‐mediated knockdown completely abolished astaxanthin‐induced NQO1 and HO‐1 upregulation. Mechanistically, astaxanthin promoted Akt phosphorylation (activation) and inhibited glycogen synthase kinase 3β (GSK‐3β) phosphorylation. Pretreatment with LY294002 (a phosphoinositide 3‐kinase/PI3K inhibitor) suppressed astaxanthin‐induced Nrf2 nuclear translocation, exacerbated ROS production, and reduced NQO1 and GSH levels. Additionally, astaxanthin blocked ox‐LDL‐induced caspase‐3 upregulation and preserved EPC migration and tube formation. Nrf2 siRNA eliminated the protective effects of astaxanthin on EPC ROS production, MMP preservation, apoptosis, and migration; tube formation was not assessed. Overall, these in vitro findings using cells from healthy donors provide mechanistic support for the potential role of astaxanthin in the PI3K/Akt/GSK‐3/Nrf2 pathway. However, the application of astaxanthin in the prevention and treatment of atherosclerotic disease requires further validation in disease‐relevant models and clinical studies, as the present study was limited to in vitro results.