Subcutaneous Administration of Apolipoprotein J-Derived Mimetic Peptide d-[113–122]apoJ Improves LDL and HDL Function and Prevents Atherosclerosis in LDLR-KO Mice

Abstract

Mimetic peptides are potential therapeutic agents for atherosclerosis. d-[113–122]apolipoprotein (apo) J (d-[113–122]apoJ) is a 10-residue peptide that is predicted to form a class G* amphipathic helix 6 from apoJ; it shows anti-inflammatory and anti-atherogenic properties. In the present study, we analyzed the effect of d-[113–122]apoJ in low-density lipoprotein receptor knockout mice(LDLR-KO) on the development of atherosclerosis and lipoprotein function. Fifteen-week-old female LDLR-KO mice fed an atherogenic Western-type diet were treated for eight weeks with d-[113–122]apoJ peptide, a scrambled peptide, or vehicle. Peptides were administered subcutaneously three days per week (200 µg in 100 µL of saline). After euthanasia, blood and hearts were collected and the aortic arch was analyzed for the presence of atherosclerotic lesions. Lipoproteins were isolated and their composition and functionality were studied. The extent of atherosclerotic lesions was 43% lower with d-[113–122]apoJ treatment than with the vehicle or scramble. The lipid profile was similar between groups, but the high-density lipoprotein (HDL) of d-[113–122]apoJ-treated mice had a higher antioxidant capacity and increased ability to promote cholesterol efflux than the control group. In addition, low-density lipoprotein (LDL) from d-[113–122]apoJ-treated mice was more resistant to induced aggregation and presented lower electronegativity than in mice treated with d-[113–122]apoJ. Our results demonstrate that the d-[113–122]apoJ peptide prevents the extent of atherosclerotic lesions, which could be partially explained by the improvement of lipoprotein functionality.

Maternal Quercetin Consumption during Pregnancy May Help Regulate Total Cholesterol/HDL-Cholesterol Ratio without Effect on Cholesterol Levels in Male Progeny Consuming High-Fat Diet

“…Indeed, this ratio has been reported to be significantly higher in ICR mice with HF diet–induced obesity than in control mice [ 35 ]. This is in accordance with our results, which showed that the total cholesterol/HDL-cholesterol ratio in the C-HF group was significantly higher than in the C-C group, while the ratios were similar in the Q-HF and C-C groups ( Figure 4 d), in which levels agree with the published values [ 36 , 37 ]. These results clearly indicate the possibility that maternal quercetin consumption may protect the next generation from disruption of cholesterol metabolism by consumption of a HF-diet, even though total cholesterol itself will increase.…”

Changes in the Composition and Function of Lipoproteins after Bariatric Surgery in Patients with Severe Obesity

“…(Sigma Diagnostics, Livonia, MI, USA) with a final concentration of 50 mU/mL in the presence of 2 mM CaCl 2 and 2 mM MgCl 2 . Size-exclusion chromatography was performed for monitoring aggregation using a Superose 6 Increase 5/150 GL column in an AKTA-FPLC system (GE Healthcare), as described [ 30 ].…”

Aggregation Susceptibility of Low-Density Lipoproteins—A Novel Modifiable Biomarker of Cardiovascular Risk

“…Notably, the 4F peptide has been shown to reduce experimental murine atherosclerosis, especially when applied during the early stages of atherosclerosis [ 106 , 107 , 108 ]. Recently, Rivas-Urbina et al showed in LDL receptor-deficient mice that a 10-residue peptide from apoJ (clusterin) inhibits LDL aggregation by binding to modified LDL particles and that it also reduces atherosclerosis [ 109 , 110 ]. Thus, the LDL surface lipid monolayer-stabilizing effect of amphipathic peptides appears not to depend on the amino acid structure of the peptide, but rather on its ability to bind to the surface lipid monolayer.…”