High dietary methionine plus cholesterol stimulates early atherosclerosis and late fibrous cap development which is associated with a decrease in GRP78 positive plaque cells

The role of homocysteine, or its precursor methionine, in the formation of fibrous caps and its association with endoplasmic reticulum (ER) stress is unclear. Homocysteine can stimulate collagen accumulation and upregulate the ER stress chaperone glucose regulated protein 78 (GRP78). The aim of this study was to determine if high dietary methionine would increase fibrous caps, and that removal of an atherogenic diet would decrease the amount of ER stressed cells. New Zealand white rabbits were fed for 2, 4, or 12 weeks an atherogenic diet [1% methionine + 0.5% cholesterol (2MC, 4MC or 12MC)]; for 4 or 12 weeks a 0.5% cholesterol diet (4Ch, 12Ch); and to study plaque regression, an MC diet for 2 or 4 weeks accompanied by 10 weeks of a normal diet (2MCr, 4MCr). Endothelial function, atherosclerosis and GRP78 positive cells were studied. Endothelial function was abolished in 4MC and atherosclerosis increased 17-fold (P < 0.05) compared with 4Ch. Fibrous caps composed 48% of total plaque area in 12MC vs. 10% in 12Ch (P < 0.01), and 12MC expressed less GRP78 plaque cells vs. 12Ch (P < 0.01). Four MCr had less plaque GRP78 cells than 12MC (P < 0.05) and less endothelial GRP78 cells (P < 0.01). In addition, GRP78 positive cells were the highest in 4MC, but decreased in all other groups (P < 0.01). GRP78 positive cells within the fibrous cap inversely correlated with cap size (r(2) = 0.9). These studies suggest that high dietary methionine could be beneficial for plaque stabilisation, and a normal diet also stabilises plaque and decreases the number of stressed plaque cells.