| Title | Evidence Supporting a Role for Endoplasmic Reticulum Stress in the Development of Atherosclerosis in a Hyperglycaemic Mouse Model. | | Author(s) | Khan MI, Pichna BA, Shi Y, Bowes AJ, Werstuck GH | | Institution | Hamilton, Ontario, Canada; mkhan@thrombosis.hhscr.org. | | Source | Antioxid Redox Signal 2009 Jun 23. | | Abstract | We have previously observed a correlation between elevated levels of vascular endoplasmic reticulum (ER) stress and accelerated atherosclerotic plaque development in chronically hyperglycaemic apolipoprotein-deficient (ApoE<sup>-/-</sup>) mice. We hypothesize that ER stress plays a causative role in diabetic atherogenesis. Here we examine the temporal relationship between the onset of hyperglycaemia, glucosamine accumulation in the vessel wall, ER stress and the development of atherosclerosis. We demonstrate, using streptozotocin-induced hyperglycaemic ApoE<sup>-/-</sup> mice, that conditions of hyperglycaemia increase intracellular glucosamine levels and endothelial ER stress levels in the endothelium prior to the onset of atherosclerosis. At 15 weeks of age hyperglycaemic mice have significantly larger atherosclerotic lesions (0.120+/-0.023 vs. 0.065+/-0.021 mm<sup>2</sup>, <i>P</i>=0.001) relative to normoglycaemic mice. Significantly, hyperglycaemia-associated accelerated atherosclerosis is observed before the onset of dyslipidemia suggesting that leveled glucose is sufficient to independently promote atherogenesis. 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 hyperglycaemia-associated ER stress in the development and progression of diabetic atherosclerosis. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19548776 |
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