Abstract
BackgroundHigh-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.ResultsNew 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.ConclusionsInfusion 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.
Highlights
High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties
We find that ETC-642 reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1) in the rabbit thoracic aorta to a similar extent as reconstituted HDL (rHDL) containing full-length apoA-I
Effect of ETC-642 on the anti-inflammatory properties and composition of rabbit HDL HDL were isolated from the rabbits that were infused with saline, rHDL and ETC-642 and assessed for their ability to inhibit TNF-a-induced expression of ICAM-1 and VCAM-1 in human coronary artery endothelial cells (HCAECs) (Figure 2)
Summary
High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. Consistent with this, in vivo studies in rabbits show that lipid free apoA-I and rHDL reduce the expression of arterial VCAM-1 and ICAM-1 in the peri-arterial cuff model of acute inflammation [3,7,8]. Due to their potent antiinflammatory properties, both HDL and apoA-I have immense therapeutic potential, but despite this there is currently no translated use to clinic. The anti-inflammatory effects of ETC-642 on chronic inflammation are, currently unknown
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