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

Mimetic peptides are potential therapeutic agents for atherosclerosis. d-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]apolipoprotein (apo) J (D-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]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-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]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-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]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-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]apoJ treatment than with the vehicle or scramble. The lipid profile was similar between groups, but the high-density lipoprotein (HDL) of d-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]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-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]apoJ-treated mice was more resistant to induced aggregation and presented lower electronegativity than in mice treated with d-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]apoJ. Our results demonstrate that the d-[¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷,¹¹⁸,¹¹⁹,¹²⁰,¹²¹,¹²²]apoJ peptide prevents the extent of atherosclerotic lesions, which could be partially explained by the improvement of lipoprotein functionality.