Oxidant resistant human apolipoprotein A-I functions similarly to the unmodified human isoform in delaying atherosclerosis progression and promoting atherosclerosis regression in hyperlipidemic mice

Abstract

Background Transgenic overexpression of apolipoprotein A-I (apoA1) has been shown to delay atherosclerosis lesion progression and promote lesion regression in mouse models; however, apoA1 is subject to oxidation by myeloperoxidase (MPO) and loss of function. The activity of oxidant resistant human apoA1 was compared to unmodified human apoA1 in mouse models of atherosclerosis progression and regression. Methods and results Human apoA1 and the MPO oxidant resistant 4WF isoform transgenic mice were bred to LDL receptor deficient (LDLr KO) mice and fed a western-type diet. High level expression of these human apoA1 isoforms did not lead to increased HDL-cholesterol levels on the LDLr KO background. In males and females, lesion progression was studied over time, and both apoA1 and 4WF transgenic mice vs. LDLr KO mice had significant and similar delayed lesion progression and reduced non-HDL cholesterol. Using time points with equivalent lesion areas, lesion regression was initiated by feeding the mice a low-fat control diet containing a microsomal triglyceride transfer protein inhibitor for 7 weeks. Lesions regressed more in the male apoA1 and 4WF transgenics vs. the LDLr KO, but the 4WF isoform was not superior to the unmodified isoform in promoting lesion regression. Conclusions Both human apoA1 and the 4WF MPO oxidant resistant apoA1 isoform delayed lesion progression and promoted lesion regression in LDLr KO mice, with more pronounced effects in males than females; moreover, the 4WF isoform functioned similarly to the unmodified human apoA1 isoform.

HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy

“…205 While these studies suggested that oxidation of apoAI Trp reduces HDL efflux capacity, subsequent in vivo studies with Ldlr −/− mice that overexpressed transgenic 4WF apoAI showed no greater lesion regression than Ldlr −/− mice overexpressing transgenic wild-type human apoAI. 206 Furthermore, 4WF apoAI transgenic mice showed less RCT to the plasma compartment than mice expressing transgenic WT human apoAI, although they did show similar overall RCT to liver and feces. 207 Other studies found that in vitro oxidation of HDL3 with either HOCl or MPO reduced HDL LCAT activity in direct correlation to the extent that apoAI Met148 and Trp72 were oxidized, but only Leu mutations of the 3 apoAI Met residues protected against MPO-induced LCAT inhibition, while deletion of the 4 apoAI Trp residues provided no protection.…”

Characterization and the cholesterol-lowering effect of dietary fiber from fermented black rice (Oryza sativa L.)

“…42 Lipoproteins play a direct role in lipid transport and clearance in the blood. 43 Apo-A1 is an HDL apolipoprotein that can esterify free TC, minimize cholesterol buildup in cells, and improve clearance of atherosclerotic plaque cholesterol. Apo-B is the major protein found in LDL-C.…”