ATTENUATION OF DIET-INDUCED ATHEROSCLEROSIS IN RABBITS WITH A HIGHLY SELECTIVE 15-LIPOXYGENASE INHIBITOR LACKING SIGNIFICANT ANTIOXIDANT PROPERTIES

1 15-Lipoxygenase (15-LO) has been implicated in the pathogenesis of a therosclerosis because of its localization in lesions and the many bio logical activities exhibited by its products. To provide further evide nce for a role of 15-LO, the effects of PD 146176 on the development o f atherosclerosis in cholesterol-fed rabbits were assessed. This novel drug is a specific inhibitor of the enzyme in vitro and lacks signifi cant non specific antioxidant properties. 2 PD 146176 inhibited rabbit reticulocyte 15-LO through a mixed noncompetitive mode with a K-i of 197 nM. The drug had minimal effects on either copper or 2,2'-azobis(2 -amidinopropane)hydrochloride (ABAP) induced oxidation of LDL except a t concentrations 2 orders higher than the K-i. 3 Control New Zealand r abbits were fed a high-fat diet containing 0.25% wt./wt. cholesterol; treated animals received inhibitor in this diet (175 mg kg(-1), b.i.d. ). Plasma concentrations of inhibitor were similar to the estimated K- i (197 nM). During the 12 week study, there were no significant differ ences in weight gain, haematocrit, plasma total cholesterol concentrat ions, or distribution of lipoprotein cholesterol. 4 The drug plasma co ncentrations achieved in vivo did not inhibit low-density lipoprotein (LDL) oxidation in vitro. Furthermore, LDL isolated from PD 146176-tre ated animals was as susceptible as that from controls to oxidation ex vivo by either copper or ABAP. 5 PD 146176 was very effective in suppr essing atherogenesis, especially in the aortic arch where lesion cover age diminished from 15+/-4 to 0% (P<0.02); esterified cholesterol cont ent was reduced from 2.1+/-0.7 to 0 mu g mg(-1) (P<0.02) in this regio n. Immunostainable lipid-laden macrophages present in aortic intima of control animals were totally absent in the drug-treated group. 6 Resu lts of these studies are consistent with a role for 15-LO in atherogen esis.