The apolipoprotein A-I mimetic peptide, ETC-642, reduces chronic vascular inflammation in the rabbit

Abstract

Background: High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. The development of peptides that mimic HDL apolipoproteins offers a promising strategy to reduce inflammatory disease. This study aimed to compare the anti-inflammatory effects of ETC-642, an apoA-I mimetic peptide, with that of discoidal reconstituted HDL (rHDL), consisting of full-length apoA-I complexed with phosphatidylcholine, in rabbits with chronic vascular inflammation.

Results: New Zealand White rabbits (n = 10/group) were placed on chow supplemented with 0.2% (w/w) cholesterol for 6-weeks. The animals received two infusions of saline, rHDL (8 mg/kg apoA-I) or ETC-642 (30 mg/kg peptide) on the third and fifth days of the final week. The infusions of rHDL and ETC-642 were able to significantly reduce cholesterol-induced expression of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the thoracic aorta (p < 0.05). When isolated rabbit HDL was pre-incubated with human coronary artery endothelial cells (HCAECs), prior to stimulation with TNF-α, it was found that HDL from ETC-642 treated rabbits were more effective at inhibiting the TNF-α-induced increase in ICAM-1, VCAM-1 and p65 than HDL isolated from saline treated rabbits (p < 0.05). There were, however, no changes in HDL lipid composition between treatment groups.

Conclusions: Infusion of ETC-642 causes anti-inflammatory effects that are comparable to rHDL in an animal model of chronic vascular inflammation and highlights that apoA-I mimetic peptides present a viable strategy for the treatment of inflammatory disease.

Figure 1

ETC-642 reduces endothelial adhesion molecule expression. Panel A: Immunohistochemical staining for ICAM-1 and VCAM-1 in representative thoracic aortic sections from cholesterol-fed NZW rabbits (n = 10 animals/group) infused with either saline, rHDL (8 mg/kg apoA-I) or ETC-642 (30 mg/kg peptide). Panel B: Endothelial expression of ICAM-1 and VCAM-1 were quantified as described in "Materials and Methods". Results are expressed as mean ± SEM. *p < 0.05 and **p < 0.01, compared to saline-infused animals.

Figure 2

The effect of isolated rabbit HDL on adhesion molecule expression and NF-κB activation in HCAECs. HCAECs were pre-incubated for 24 hrs with rHDL or HDL isolated from the plasma of rabbits injected with either saline, rHDL or ETC-642 (n = 10), then stimulated with TNF-α (1 ng/ml) for 5 hrs. ICAM-1, VCAM-1 and p65 mRNA levels were quantified as described in "Materials and Methods". Results expressed as mean ± SEM from triplicate in vitro experiments. *p < 0.05 and **p < 0.01, compared to TNF-α stimulated control cells.