Microphage apoptosis is a critical event in atherosclerotic lesions in patients with diabetes. In the present investigation, high glucose treatment inhibited Akt phosphorylation and activated caspase 3 in primary peritoneal macrophage, leading to cell apoptosis. Hypoxia prolonged macrophage survival in high glucose condition. Extracellular polysaccharide from Bordetella species (EPS) further decreased cell apoptosis in response to high glucose during hypoxia. Under high glucose and hypoxic condition, EPS treatment promoted caveolin-1 phosphorylation by recognizing TLR4. Caveolin-1 phosphorylation elevated membrane Glut 1 level to accelerate glucose consumption, which should be the reason for protective effect of EPS on macrophage exposed to high glucose. Further investigation demonstrated that TLR4-dependent caveolin-1 phosphorylation induced by EPS promoted association of caveolin-1 with TLR4, which should be critical for activation of TLR4 signaling pathway. (C) 2015 Elsevier Inc. All rights reserved.