Effect of hyperglycemia and hyperlipidemia on atherosclerosis in LDL receptor-deficient mice - Establishment of a combined model and association withheat shock protein 65 immunity

Diabetes and atherosclerosis have been proposed to be influenced by immune and autoimmune mechanisms. A common incriminated antigen in both disorders is the heat shock protein (HSP)-60/65. Ln the current study, we established a model combining hyperglycemia with hyperlipidemia in LDL receptor-defici ent: (LDL-RD) mice and assessed its possible influences on Lipid profile, H SP60/65, and atherogenesis. LDL-RD mice R-ere injected either with streptoz otocin to induce hyperglycemia or with citrate buffer (control). When hyper glycemia was induced, both study groups were challenged with a high-fat (We stern) diet for 6 weeks. Plasma fasting glucose, lipid profile, and antibod y levels to HSP65 and oxidized LDL were assessed. At death, the spleens fro m both groups were evaluated for their proliferative response to HSP65 and the consequent cytokine production. The extent of atherosclerosis was asses sed at the aortic sinus. Plasma glucose, cholesterol, and triglyceride leve ls were elevated in mice injected with streptozotocin compared with control mice. Atherosclerotic lesions were significantly larger in the streptozoto cin-injected hyperglycemic LDL-RD mice (132 +/- 23 x 10(5) mu m(2)) in comp arison to their normoglycemic litter-mates (20 +/- 6.6 x 105 mu m(2); P < 0 .0001). Both humoral and cellular immune response to HSP65 was more pronoun ced in streptozotocin-injected mice. When challenged with HSP65 in vitro, s plenocytes hom streptozotocin-injected mice favored the production of the T -helper (TH)-1 cytokine gamma-interferon. In conclusion, we have establishe d a mouse model that combines hyperglycemia with diet-induced hyperlipidemi a in LDL-RD mice and studied its effect on atherosclerosis progression. The accelerated atherosclerotic process is associated with heightened immune r esponse to HSP65 and a shift to a TH1 cytokine profile.