| First Author | McAlpine CS | Year | 2012 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 32 |
| Issue | 1 | Pages | 82-91 |
| PubMed ID | 21998135 | Mgi Jnum | J:195980 |
| Mgi Id | MGI:5486295 | Doi | 10.1161/ATVBAHA.111.237941 |
| Citation | McAlpine CS, et al. (2012) Endoplasmic reticulum stress and glycogen synthase kinase-3beta activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis. Arterioscler Thromb Vasc Biol 32(1):82-91 |
| abstractText | OBJECTIVE: The goal of this study was to examine the role of endoplasmic reticulum (ER) stress signaling and the contribution of glycogen synthase kinase (GSK)-3beta activation in hyperglycemic, hyperhomocysteinemic, and high-fat-fed apolipoprotein E-deficient (apoE(-/-)) mouse models of accelerated atherosclerosis. METHODS AND RESULTS: Female apoE(-/-) mice received multiple low-dose injections of streptozotocin (40 mug/kg) to induce hyperglycemia, methionine-supplemented drinking water (0.5% wt/vol) to induce hyperhomocysteinemia, or a high-fat (21% milk fat+0.2% cholesterol) diet to induce relative dyslipidemia. A subset of mice from each group was supplemented with sodium valproate (625 mg/kg), a compound with GSK3 inhibitory activity. At 15 and 24 weeks of age, markers of ER stress, lipid accumulation, GSK3beta phosphorylation, and GSK3beta activity were analyzed in liver and aorta. Atherosclerotic lesions were examined and quantified. Hyperglycemia, hyperhomocysteinemia, and high-fat diet significantly enhanced GSK3beta activity and also increased hepatic steatosis and atherosclerotic lesion volume compared with controls. Valproate supplementation blocked GSK3beta activation and attenuated the development of atherosclerosis and the accumulation of hepatic lipids in each of the models examined. The mechanism by which GSK3beta activity is regulated in these models likely involves alterations in phosphorylation at serine 9 and tyrosine 216. CONCLUSIONS: These findings support the existence of a common mechanism of accelerated atherosclerosis involving ER stress signaling through activation of GSK3beta. Furthermore, our results suggest that atherosclerosis can be attenuated by modulating GSK3beta phosphorylation. |
