Reduced progression of atherosclerosis in apolipoprotein E-deficient mice treated with lacidipine is associated with a decreased susceptibility of low-density lipoprotein to oxidation.
A study has been carried out in the apolipoprotein (apo) E-deficient mouse to investigate the activity of lacidipine (a calcium antagonist with antioxidant properties) in inhibiting the development of atherosclerotic lesions; of particular interest were changes in the susceptibility of low-density lipoproteins (LDL) to oxidation. Mice receiving a Western-type diet to accelerate the development of atherosclerosis were treated orally with vehicle or lacidipine at 3 or 10 mg/kg/day for 8 weeks. Lacidipine treatment (at 3 or 10 mg/kg) had no effect on the plasma lipid profile. However, a significant (P < 0.01) dose-related reduction of 43 and 50% of the aortic lesion area in respect to vehicle-treated mice was observed. Moreover, the resistance of mouse plasma LDL to undergo lipid peroxidation was significantly (P < 0.01) increased in apo E-deficient mice treated with lacidipine. The native LDL-like particle, derived from apo E-deficient mice treated with lacidipine, contained significantly lower concentrations of malonyldialdehyde than the vehicle-treated control group (P < 0.01). After exposure to human umbilical vein endothelial cells, LDL-like particle vitamin E levels (expressed as area under the curve; AUC), were significantly higher (P < 0.01) in both the 3 and 10 mg/kg lacidipine-treated groups, in comparison with the vehicle-treated control animals. We conclude that lacidipine reduced the extent of the atherosclerotic area in hypercholesterolaemic apo E-deficient mice, and that this reduction may be associated with the capacity of the drug to decrease the susceptibility of LDL to oxidation.
Cristofori
Patrizia
P
GlaxoSmithKline S.p.A, Medicine Research Centre, Verona, Italy. patrizia.g.cristofori@gsk.com
Crivellente
Federica
F
Campagnola
Mario
M
Pasini
Anna Fratta
AF
Garbin
Ulisse
U
Rigoni
Anna
A
Tosetti
Maria
M
Turton
John
J
Faustinelli
Ivo
I
Cominacini
Luciano
L
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000627:therapeutic use*; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D014810:Vitamin E / Q000378:metabolism
D000975:Antioxidants; D001057:Apolipoproteins E; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D008077:Lipoproteins, LDL; D014810:Vitamin E; C060285:lacidipine; D008315:Malondialdehyde