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.
Highlights
Cardiovascular disease (CVD) is the leading cause of mortality worldwide; coronary artery disease of atherosclerotic origin is the most common expression of CVD
The area of proximal atherosclerosis in d-[113–122]apolipoprotein J (apoJ)-treated mice was 40%–45% lower (55,305 ± 19,155 μm2/section) than in control (92,549 ± 18,880 μm2/section) or scramble (97,144 ± 36,140 μm2/section) mice
PBeiopmtoildeceuldese2v0e2l0o, p10e,dx less advanced atherosclerotic lesions and more restricted aortic valve attachm6 eonf t1s9 compared with the larger lesions that extended to the free aortic wall in both Control and Scramble mice
Summary
Cardiovascular disease (CVD) is the leading cause of mortality worldwide; coronary artery disease of atherosclerotic origin is the most common expression of CVD. Even with normal lipid levels and in the absence of other classical CVD risk factors, such as hypertension, diabetes, obesity or smoking habits, cardiovascular events can occur. This is known as residual cardiovascular risk, and part of this risk is of lipid origin [2]. Regarding high-density lipoproteins (HDL), these particles play a protective role against atherosclerotic development through several mechanisms that include, among others, the reverse transport of the cholesterol accumulated in arterial lesions and the inhibition of the oxidative modification of LDL [5]. Increased susceptibility of LDL to oxidation or to aggregation [6], as well as a loss of the protective properties of HDL, has been related to accelerated atherosclerosis [7]
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