Abstract 18114: Efficacy of Apolipoprotein A-IV as a Vascular Anti-Inflammatory and Anti-Oxidant Agent

Abstract

Objective: Apolipoprotein (apo) A-IV, the 3rd most abundant HDL apolipoprotein in human plasma, has anti-inflammatory properties in animal models of colitis and LPS-induced systemic inflammation. This study investigates the ability of apoA-IV to inhibit acute vascular inflammation in the NZW rabbit. Methods: A non-occlusive peri-arterial carotid collar was inserted into normocholesterolemic NZW rabbits (mean weight 3 Kg) 24 h after administering a single intravenous (iv) infusion of either saline or lipid-free apoA-IV (1 mg/kg). The animals were sacrificed 24 h post-collar insertion. Carotid arteries were extracted and analysed immunohistochemically for endothelial expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and intima/media neutrophil infiltration (CD18+ cells). Human coronary artery endothelial cells (HCAECs) were pre-incubated for 16 h with discoidal reconstituted HDL (rHDL) containing phosphatidylcholine complexed with apoA-IV (final apoA-IV concentration 10 µM/L), then stimulated for a further 5 h with tumour necrosis factor α (TNF- α) (0.2 ng/ml). Cell surface VCAM-1 and ICAM-1 expression was measured by flow cytometry. VCAM-1 and ICAM-1 mRNA levels and the mRNA level of the anti-oxidant and anti-apoptotic enzyme 3β-hydroxysteroid-D24 reductase (DHCR24) were quantified by qPCR. Results: Relative to the saline-infused animals, a single iv infusion of lipid-free apoA-IV decreased collar-induced neutrophil infiltration by 74% and endothelial expression of ICAM-1 and VCAM-1 by 75% and 68%, respectively. Pre-incubation of TNF-α stimulated HCAECs with rHDL reduced ICAM-1 protein and mRNA levels by 34% and 48%, respectively. VCAM-1 protein and mRNA levels were decreased by 61% and 55%, respectively. Pre-incubation of HCAECs with rHDL increased DHCR24 mRNA levels 2.6-fold. Conclusion: ApoA-IV has potent vascular anti-inflammatory and anti-oxidant properties in vitro and in vivo .