5-Aminolevulinic Acid Attenuates Atherosclerotic Plaque Progression in Low-Density Lipoprotein Receptor-Deficient Mice by Heme Oxygenase-1 Induction

Background: Recently, 5-aminolevulinic acid (ALA) has been reported to modulate inflammatory development via an antioxidant effect. Hence, the aim of this study was to determine the anti-atherosclerotic effect of ALA. Methods and Results: Low-density lipoprotein (LDL) receptor knockout mice were fed the following diets for 24 weeks: normal diet (n=6); 1.25% cholesterol diet (high-cholesterol diet, HCD; n=7); HCD+ALA (46 mg/kg/day; n=10); and HCD+ezetimibe (5 mg/kg/day; n=10). At 40 weeks, HCD+ALA had reduced LDL cholesterol (320±68 vs. 379±49 mg/dL), triglyceride (141±44 vs. 195±49 mg/dL) and oxidized LDL (380±40 vs. 422±64 pg/mL) compared with HCD only. En face lesion area for the entire aortic surface was significantly smaller in mice that received HCD+ALA than in mice that received only HCD (32±5% vs. 39±4%, P<0.05). ALA intake exogenously increased tissue heme oxygenase-1 (HO-1) level in plaque composite tissue of the carotid arterial wall compared with HCD only (18±8 vs. 12±3 pg/μL, P<0.05), and HO-1-positive plaque showed modest NADPH oxidase 4 expression. Conclusions: ALA intake induces exogenous production of HO-1 at plaque sites, and improves lipid profiles and attenuation of atherosclerotic plaque progression in vivo.