Evidence Supporting a Role for Endoplasmic Reticulum Stress in the Development of Atherosclerosis in a Hyperglycaemic Mouse Model

We previously observed a correlation between elevated levels of vascular endoplasmic reticulum (ER) stress and accelerated atherosclerotic plaque development in chronically hyperglycemic apolipoprotein-deficient (ApoE(-/-)) mice. We hypothesize that ER stress plays a causative role in diabetic atherogenesis. Here we examine the temporal relation between the onset of hyperglycemia, glucosamine accumulation in the vessel wall, ER stress, and the development of atherosclerosis. We demonstrate, by using streptozotocin-induced hyperglycemic ApoE(-/-) mice, that conditions of hyperglycemia increase intracellular glucosamine levels and endothelial ER stress levels in the endothelium before the onset of atherosclerosis. At 15 weeks of age, hyperglycemic mice have significantly larger atherosclerotic lesions (0.120 +/- 0.023 vs. 0.065 +/- 0.021 mm2; p = 0.001) relative to normoglycemic mice. Significantly, hyperglycemia-associated accelerated atherosclerosis is observed before the onset of dyslipidemias, suggesting that leveled glucose is sufficient to promote atherogenesis independently. Diagnostic markers of elevated ER-stress levels are increased in macrophage-derived foam cells in early and advanced atherosclerotic lesions. Dietary supplementation with valproate, a small branched-chain fatty acid that interferes with ER-stress signaling, significantly attenuates accelerated atherogenesis in this model. Together, these data are consistent with a causative role for hyperglycemia-associated ER stress in the development and progression of diabetic atherosclerosis.