Abstract

ApoA-I mimetic peptides are currently being developed as possible new agents for the treatment of cardiovascular disease based on their ability to promote cholesterol efflux and their other beneficial anti-atherogenic properties. Many of these peptides, however, have been reported to cause transient hypertriglyceridemia due to inhibition of lipolysis by Lipoprotein Lipase (LPL). We describe a novel bi-helical amphipathic peptide (C-II-a) that contains an amphipathic helix (18A) for binding to lipoproteins and stimulating cholesterol efflux, as well as a motif based on the last helix of apoC-II that activates lipolysis by LPL. The C-II-a peptide promoted cholesterol efflux from ABCA1-transfected BHK cells similar to apoA-I mimetic peptides. Furthermore, it was shown in vitro to be comparable to the full-length apoC-II protein in activating lipolysis by LPL. When added to serum from a patient with apoC-II deficiency, it restored normal levels of LPL-induced lipolysis and also enhanced lipolysis in serum from patients with Type IV and Type V hypertriglyceridemia. Intravenous injection of C-II-a (30mg/kg) in ApoE-KO mice resulted at 4h in a significant reduction of plasma cholesterol and triglycerides of 38±6% and 85±7%, respectively. When co-injected with the 5A peptide (60mg/kg), the C-II-a (30mg/kg) peptide was found to completely block in C57Bl/6 mice the hypertriglyceridemic effect of the 5A peptide. In summary, C-II-a is a novel peptide based on apoC-II, which promotes cholesterol efflux and lipolysis and may, therefore, be useful for the treatment of apoC-II deficiency and other forms of hypertriglyceridemia.