1.
15-Lipoxygenase (15-LO) has been implicated in the pathogenesis of
atherosclerosis because of its localization in lesions and the many
biological activities exhibited by its products. To provide further evidence for a role of 15-LO, the effects of
PD 146176 on the development of
atherosclerosis in
cholesterol-fed rabbits were assessed. This novel
drug is a specific inhibitor of the
enzyme in vitro and lacks significant non specific
antioxidant properties. 2.
PD 146176 inhibited rabbit reticulocyte 15-LO through a mixed noncompetitive mode with a Ki of 197 nM. The
drug had minimal effects on either
copper or 2,2'-azobis(2-amidinopropane)hydrochloride (
ABAP) induced oxidation of
LDL except at concentrations 2 orders higher than the Ki. 3. Control New Zealand rabbits 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 Ki (197 nM). During the 12 week study, there were no significant differences in
weight gain haematocrit, plasma total
cholesterol concentrations, or distribution of
lipoprotein cholesterol. 4. The
drug plasma concentrations achieved in vivo did not inhibit
low-density lipoprotein (
LDL) oxidation in vitro. Furthermore,
LDL isolated from PD 146176-treated animals was as susceptible as that from controls to oxidation ex vivo by either
copper or
ABAP. 5.
PD 146176 was very effective in suppressing
atherogenesis, especially in the aortic arch where lesion coverage diminished from 15 +/- 4 to 0% (P < 0.02); esterified
cholesterol content was reduced from 2.1 +/- 0.7 to 0 micrograms mg-1 (P < 0.02) in this region. Immunostainable
lipid-laden macrophages present in aortic intima of control animals were totally absent in the
drug-treated group. 6. Results of these studies are consistent with a role for 15-LO in
atherogenesis.