Glucosamine-induced endoplasmic reticulum dysfunction is associated with accelerated atherosclerosis in a hyperglycemic mouse model.
Diabetes is a major independent risk factor for cardiovascular disease and stroke; however, the molecular and cellular mechanisms by which diabetes contributes to the development of vascular disease are not fully understood. Our previous studies demonstrated that endoplasmic reticulum (ER) stress-inducing agents, including homocysteine, promote lipid accumulation and activate inflammatory pathways-the hallmark features of atherosclerosis. We hypothesize that the accumulation of intracellular glucosamine observed in diabetes may also promote atherogenesis via a mechanism that involves ER stress. In support of this theory, we demonstrate that glucosamine can induce ER stress in cell types relevant to the development of atherosclerosis, including human aortic smooth muscle cells, monocytes, and hepatocytes. Furthermore, we show that glucosamine-induced ER stress dysregulates lipid metabolism, leading to the accumulation of cholesterol in cultured cells. To examine the relevance of the ER stress pathway in vivo, we used a streptozotocin-induced hyperglycemic apolipoprotein E-deficient mouse model of atherosclerosis. Using molecular biological and histological techniques, we show that hyperglycemia is associated with tissue-specific ER stress, hepatic steatosis, and accelerated atherosclerosis. This novel mechanism may not only explain how diabetes and hyperglycemia promote atherosclerosis, but also provide a potential new target for therapeutic intervention.
Werstuck
Geoff H
GH
Henderson Research Centre, 711 Concession St., Hamilton, Ontario, Canada L8V 1C3. gwerstuck@thrombosis.hhscr.org
Khan
Mohammad I
MI
Femia
Giuseppe
G
Kim
Anna J
AJ
Tedesco
Vivienne
V
Trigatti
Bernardo
B
Shi
Yuanyuan
Y
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000150:complications* / Q000503:physiopathology*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005944:Glucosamine / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000473:pathology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000378:metabolism
D001057:Apolipoproteins E; D016328:NF-kappa B; D005944:Glucosamine