STUDY OF CAUSES UNDERLYING THE LOW ATHEROSCLEROTIC RESPONSE TO DIETARY HYPERCHOLESTEROLEMIA IN A SELECTED STRAIN OF RABBITS

We have recently characterized a strain of rabbits that shows a low at herosclerotic response (LAR) to dietary hypercholesterolemia in contra st to the usual high atherosclerotic response (HAR) of rabbits [1]. Pr esently, we have focused on three well established and important stage s of atherogenesis, i.e., monocyte adhesion to endothelium, cell media ted peroxidative modification of lipoproteins and induction of a recep tor that recognizes modified low density lipoprotein (LDL). The result s obtained show that(1) beta-very low density lipoprotein (beta-VLDL) from LAR and HAR rabbits enhanced monocyte adhesion to endothelial cel ls to the same extent; (2) Cell mediated peroxidation of LDL and beta- VLDL, tested by loss of alpha-tocopherol and formation of thiobarbitur ic acid reacting substances (TEARS), was compared using macrophages, f ibroblasts and smooth muscle cells (SMC) of LAR and HAR rabbits and no significant differences were found; (3) Induction of scavenger recept or by phorbol ester (phorbol 12-myristate 13-acetate (PMA)) and platel et-derived growth factor-BE (PDGF-EE) was determined in SMC or fibrobl asts from LAR and HAR rabbits using -dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate-acetylated LDL (DiL-acLDL). We found a si gnificantly higher uptake of DiI-acLDL in SMC and fibroblasts derived from HAR rabbits as compared with cells from LAR rabbits. Similar resu lts were also obtained with [I-125]-acLDL in fibroblasts from LAR and HAR rabbits with respect to cellular lipoprotein degradation after PMA pretreatment. Even though the attenuated atherosclerotic response to hypercholesterolemia of LAR rabbits may have multiple underlying cause s, the most prominent so far is an apparent difference in inducibility of scavenger receptor in SMC and fibroblasts.