EXOGENOUS OXIDIZED LOW-DENSITY-LIPOPROTEIN INJURES AND ALTERS THE BARRIER FUNCTION OF ENDOTHELIUM IN RATS IN-VIVO

Oxidation converts low-density lipoprotein (LDL) into a cytotoxin in v itro. Oxidized LDL exists in vivo in atherosclerotic lesions and possi bly in plasma. Many cell functions are altered in vitro by oxidized LD L, but few have been examined in vivo. To test whether oxidized LDL co uld injure endothelial cells and alter endothelial permeability to mac romolecules in vivo, we infused oxidized LDL, native LDL, or their sol vent intravenously into rats. Subsequently, endothelial cell injury an d proliferation were measured, and the transport into the aorta wall o f the macromolecule horseradish peroxidase (HRP) was quantified. Trans port data were analyzed using mathematical models of macromolecular tr ansport; parameters were estimated by optimally fitting model-predicte d HRP concentrations to experimental data. Compared with native LDL or solvent control infusion, oxidized LDL infusion increased (1) the num ber of injured aortic endothelial cells fivefold to sixfold at 36 hour s, (2) proliferation of endothelial cells at 48 hours, (3) intimal and medial accumulations of HRP twofold to threefold at 48 hours, and (4) the permeability coefficient of the endothelium to HRP fourfold to fi vefold at 48 hours. Hence, oxidized LDL administered in vivo can injur e the endothelium, despite the presence of endogenous antioxidants, co mpromising the function of the endothelium as a permeability barrier.