TY - JOUR
T1 - Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties
AU - Sendobry, Sandra M.
AU - Cornicelli, Joseph A.
AU - Welch, Kathryn
AU - Bocan, Thomas
AU - Tait, Bradley
AU - Trivedi, Bharat K.
AU - Colbry, Norman
AU - Dyer, Richard D.
AU - Feinmark, Steven J.
AU - Daugherty, Alan
PY - 1997
Y1 - 1997
N2 - 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 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 at concentrations 2 orders higher than the K(i). 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 K(i) (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 μg 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.
AB - 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 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 at concentrations 2 orders higher than the K(i). 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 K(i) (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 μg 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.
KW - Atherosclerosis
KW - Endothelium
KW - Lipoprotein
KW - Lipoxygenase
KW - Macrophages
KW - Oxidation
UR - http://www.scopus.com/inward/record.url?scp=8244253670&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=8244253670&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0701007
DO - 10.1038/sj.bjp.0701007
M3 - Article
C2 - 9105693
AN - SCOPUS:8244253670
SN - 0007-1188
VL - 120
SP - 1199
EP - 1206
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 7
ER -