A reconstituted HDL containing V156K or R173C apoA-I exhibited anti-inflammatory activity in apo-E deficient mice and showed resistance to myeloperoxidase-mediated oxidation

Abstract

It has been hypothesized that blood infusion of reconstituted HDL (rHDL) is a possible therapeutic strategy for the treatment of coronary artery disese. To compare short-term anti-inflammatory activity of wildtype (WT) apoA-I and point mutants, each rHDL containing WT, V156K, or R173C was infused into apo-E deficient atherosclerotic mice. Each rHDL was injected via the tail vein at a dosage of 120 mg/kg of body weight in 0.4 ml of tris-buffered saline (TBS), and blood was then collected at 24 and 48 h post-injection. Although regression activity was observed in each of the rHDL infused groups, a 30% reduction in the lipid-stained area of the aortic sinus was observed in the V156K and R173C-rHDL groups when compared to that of the WT-rHDL group, and this reduction was well correlated with an approximately 60% reduction in the accumulation of macrophages in the lesion area. Additionally, the groups that received the V156K and R173C-rHDL treatments showed smaller increases in the GOT, GPT, interleukin-6, myeloperoxidase (MPO) and lipid hydroperoxide (LPO) serum levels than those that received the WT-rHDL treatment. In addition, the strongest serum paraoxonase and ferric reducing ability was observed in the V156K and R173C-rHDL groups. In vitro nitration and chlorination of apoA-I by MPO treatment revealed that V156K-rHDL and R173C-rHDL were less susceptible to chlorination. Furthermore, rHDL treatment inhibited cellular uptake of oxidized LDL by macrophage cells and the production of proatherogenic species in culture media. In conclusion, blood infusions of the rHDLs exerted in vivo regression activity with anti-inflammatory and antioxidant activity in apo-E deficient mice and THP-1 cells, especially in those that were treated with V156K and R173C apoA-I.

Enhanced Delivery of Adenovirus, Using Proteoliposomes Containing Wildtype or V156K Apolipoprotein A-I and Dimyristoylphosphatidylcholine

“…Recombinant V156K mutant behaved differently from the wild type in both lipid- free and lipid-bound states in vitro and in vivo (Cho et al, 2006(Cho et al, , 2007. V156K exhibited enhanced potent antioxidant and antiinflammatory activity, and an antiatherosclerotic effect (Cho and Kim, 2009) with different movement of the hinge domain of apoA-I as compared with wild type (Han et al, 2005). In addition, numerous clinical observations have shown that higher apoA-I serum concentrations result in lower cardiovascular risk (Walldius and Jungner, 2007).…”

“…WT human apoA-I is composed of a single polypeptide chain of 243 amino acids and a principal protein component of HDL that is known to perform a crucial role in the reverse cholesterol transport pathway through its antioxidant and antiinflammatory activities (Barter et al, 2004;Ansell et al, 2005). A point mutant of apoA-I, V156K, showed unique structural and functional properties in vitro (Han et al, 2005), and V156K-rHDL has been shown to exert antioxidant effects in hypercholesterolemic C57BL=6 mice (Cho et al, 2006(Cho et al, , 2007 and antiatherosclerotic activity in apoE-deficient mice (Cho and Kim, 2009).…”

Biomedicinal implications of high-density lipoprotein: its composition, structure, functions, and clinical applications

“…It demonstrated potent antioxidant activity and anti-inflammatory activity both in vivo and in vitro (20), as well as an in vivo anti-atherosclerotic effect (64,65). The pharmaceutical effects of V156K-rHDL were compared directly to WT-rHDL and R173C-rHDL.…”

Genetic control of apoprotein A-I and atheroprotection: some insights from inbred strains of mice

“…The most robust evidence for the atheroprotective function of HDL derives from the overexpression of apoA-I by transgenesis in mice and rabbits, which leads to a reduction in atherosclerosis, and the elimination of apoA-I expression in mouse models, which results in an accentuation of atherosclerosis. A few rare mutants of human apoA-I either enhance (ApoA-I Milano ) [5] or impair (ApoA-I Pisa or ApoA-I FIN ) [6] the function of apoA-I and HDL. Indeed, apoA-I Milano has been infused into patients to promote regression of atherosclerosis [7, 8].…”