MDR1 gene expression in normal and atherosclerotic human arteries

Recent studies have shown that a membrane p-glyco-protein, encoded by MDR1 gene, is involved in the transport of free cholesterol from the plasma memb rane to endoplasmic reticulum, the site of cholesterol esterification by ac yl-CoA:cholesterol acyltransferase (ACAT). Moreover, results deriving from our previous studies have shown that the rate of cell proliferation was pos itively correlated with cholesteryl ester levels as well as with ACAT and M DR1 gene expression. In this study, lipid content and the expression of the genes involved in cholesterol metabolism such as hydroxy-methylglutaryl co enzyme A reductase (HMGCoA-R), low-density lipo-protein receptor (LDL-R), A CAT and MDR1 have been investigated in control and atherosclerotic arteries . The results have shown that the levels of cholesteryl ester increase with the age of cadaveric donors in arteries prone to atherosclerosis (abdomina l aorta, superficial femoral artery) and become predominant in advanced ath erosclerotic lesions. The mRNA levels of ACAT and MDR1 showed the same age correlation, reaching the highest values in atherosclerotic specimens. Thes e results suggest that MDR1 may be involved in the accumulation of intracel lular cholesterol ester levels found in atherosclerotic lesions. Moreover, the levels of HMGCoA-R, LDL-R and ACAT gene expressions progressively incre ased with the age of cadaveric donors; conversely, in atherosclerotic speci mens, the mRNA levels of HMGCoA-R and LDL-R drastically decreased while ACA T gene expression reached its maximum. These findings suggest a reactivatio n of normal homeostatic regulation of cholesterol in advanced and complicat ed lesions.