In Vivo Formation of Oxidatively Modified Low-Density Lipoprotein and Its Inhibitory Effects on Cholesteryl Ester Hydrolases in the Rat.

Abstract

In order to elucidate the mechanisms pertaining to the interrelation between atherosclerotic changes and lipid peroxides in the aorta, we examined the effects of increased lipid peroxides in plasma and in the aorta on cholesteryl ester-hydrolyzing enzymes by feeding rats a small quantity of autoxidized linoleic acid hydroperoxide (LHPO). In LHPO-fed rats, plasma and hepatic lipid peroxides were elevated in an inverse relation to vitamin E levels. Aortic cholesteryl ester content was increased by 42% in the treated rats along with a 65% increase in the lipid peroxide content. The activities of acid (AL) and neutral (NL) cholesteryl ester hydrolases of the LHPO group were reduced in aorta, mononuclear leukocytes, hepatic lysosomes, and microsomes compared with those of the control group. The addition of purified linoleate hydroperoxide and serum lipid peroxides, and low-density lipoprotein (LDL) isolated from LHPO-fed rats also showed a dose-dependent inhibition of both AL and NL activities of mononuclear leukocytes in vitro. The LDL showed high lipid peroxide values that were about 6 times over the normal LDL value and exhibited characteristics typical of oxidatively modified LDL; that is to say, the net negative charges increased along with a degradation of the tertiary structure of the apolipoprotein. The results 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 cholesteryl ester hydrolases and allowing an increase in cellular cholesteryl esters. Oxidatively modified LDL thereby becomes one of the factors that initiates and causes the development of atherosclerotic changes in the aorta.