Abstract 1312: Dietary Supplementation With Sodium Valproate Attenuates Lesion Development In Hyperglycemic Apolipoprotein E-deficient Mice Journal Articles uri icon

  •  
  • Overview
  •  
  • Research
  •  
  • Identity
  •  
  • Additional Document Info
  •  
  • View All
  •  

abstract

  • Diabetes mellitus 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. We have shown that conditions of hyperglycemia are associated with accumulation of glucosamine, a down stream metabolite of glucose, in specific cell types. Our findings indicate that elevated levels of intracellular glucosamine can promote endoplasmic reticulum (ER) stress in vascular cells leading to inflammation and lipid accumulation - the hallmark features of atherosclerosis. Treatment with valproic acid, a small branch chain fatty acid, can protect cultured cells from glucosamine-induced lipid accumulation by a mechanism that appears to involve inhibition of the signaling factor glycogen synthase kinase (GSK)-3. Here we evaluate the hypothesis that valproic acid can reduce the development and progression of atherosclerotic lesions in a hyperglycemic mouse model of accelerated atherosclerosis. Female apoE −/− mice were made hyperglycemic with multiple low dose injections of streptozotocin. At 15 weeks of age, hyperglycemic mice had accelerated the development of atherosclerotic lesions at the aortic root compared to normoglycemic mice. Mice fed a diet supplemented with 625 mg/kg sodium valproate had significantly reduced lesion volume relative to unsupplemented controls (4.98±0.76 versus 8.62±1.23 μm 3 , P <0.05, n =9). Valproate supplementation had no apparent effect on plasma glucose or plasma lipid levels or on the expression of diagnostic markers of ER stress in the atherosclerotic plaque. Significant reductions were observed in total hepatic lipids (>50.4%, P <0.05, n =3) and hepatic GSK-3β activity (>55.8%, P <0.05, n =3) in mice fed the valproate diet. In conclusion, dietary supplementation with low levels of sodium valproate significantly attenuates atherogenesis in hyperglycemic apoE −/− mice. This effect may involve the previously observed ability of valproate to attenuate the downstream effects of ER stress, such as GSK-3β activity.

publication date

  • October 16, 2007