Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia.

Abstract

Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.Cg-<i>Lep</i>^<i>ob</i> /J (<i>ob/ob</i>) mice. Vaccination with the E3 (³²EPKSRFAMLD⁴¹) peptide significantly reduces circulating levels of triglycerides, LDL-C, and small dense (sd)-LDL-C in <i>ob/ob</i> mice and decreases obese-induced fatty liver. Moreover, E3 vaccination does not induce cytotoxicity in <i>ob/ob</i> mice. Interestingly, the effect of E3 vaccination on dyslipidemia attenuates development of atherosclerosis in B6.KOR/StmSlc-<i>Apoe</i>^<i>shl</i> mice fed a high-cholesterol diet, which represent a model of severe familial hypercholesterolemia (FH) caused by ApoE loss of function. Taken together, ANGPTL3 vaccination could be an effective therapeutic strategy against dyslipidemia and associated diseases.