IN-VIVO FORMATION OF OXIDATIVELY MODIFIED LOW-DENSITY-LIPOPROTEIN ANDITS INHIBITORY EFFECTS ON CHOLESTERYL ESTER HYDROLASES IN THE RAT

In order to elucidate the mechanisms pertaining to the interrelation b etween atherosclerotic changes and lipid peroxides in the aorta, we ex amined the effects of increased lipid peroxides in plasma and in the a orta on cholesteryl ester-hydrolyzing enzymes by feeding rats a small quantity of autoxidized linoleic acid hydroperoxide (LHPO). In LHPO-fe d rats, plasma and hepatic lipid peroxides were elevated in an inverse relation to vitamin E levels. Aortic cholesteryl ester content was in creased by 42% in the treated rats along with a 65% increase in the li pid peroxide content. The activities of acid (AL) and neutral (NL) cho lesteryl ester hydrolases of the LHPO group were reduced in aorta, mon onuclear leukocytes, hepatic lysosomes, and microsomes compared with t hose of the control group. The addition of purified linoleate hydroper oxide and serum lipid peroxides, and low-density lipoprotein (LDL) iso lated from LHPO-fed rats also showed a dose-dependent inhibition of bo th AL and NL activities of mononuclear leukocytes in vitro. The LDL sh owed high lipid peroxide values that were about 6 times over the norma l LDL value and exhibited characteristics typical of oxidatively modif ied LDL; that is to say, the net negative charges increased along with a degradation of the tertiary structure of the apolipoprotein. The re sults suggest that an increase in blood lipid peroxides may alter LDL into an oxidatively modified form that is then incorporated into cells via scavenger receptors, thus inhibiting the intracellular cholestery l ester hydrolases and allowing an increase in cellular cholesteryl es ters. Oxidatively modified LDL thereby becomes one of the factors that initiates and causes the development of atherosclerotic changes in th e aorta.