Abstract 568: ApoE-/- Mice Lacking Hemopexin Develop Aggravated Atherosclerosis via Mechanisms That Include Altered High Density Lipoprotein Inflammatory Properties and Macrophage Function

Abstract

Introduction: The etiology of atherosclerosis is multi-faceted. Atherosclerotic plaques are characterized by the accumulation of lipid-laden macrophages, reactive oxygen species (ROS) and pro-inflammatory lipoproteins. Recent studies suggest that the anti- or pro-inflammatory nature of high density lipoprotein (HDL) may be a more sensitive indicator of atherosclerosis than HDL-cholesterol (HDL-C) levels alone. Our laboratory previously reported that hemopexin (Hx) is significantly increased and associated with pro-inflammatory HDL under atherogenic conditions. Hx is a heme scavenging protein which together with macrophages, plays a role in mitigating heme and ROS mediated oxidative damage. However, the role of Hx in atherosclerosis is not known. Hypothesis: We hypothesized that absence of Hx plays an important role in the accumulation of pro-inflammatory HDL, macrophage function, and the development of atherosclerosis. Methods: We crossed Hx -/- mice onto the apoE -/- background (HxE -/- mice). Chow diet fed HxE -/- and apoE -/- mice (n=10-15) were analyzed for lipoprotein inflammatory properties, macrophage gene expression, and atherosclerosis. Results: Serum ROS and heme (p<0.05) were significantly higher in the HxE -/- mice. Livers of HxE -/- mice showed increased lipid peroxides (p<0.001), and ex vivo monocyte chemotactic assays indicated that HDL from HxE -/- mice was more pro-inflammatory (p<0.002). Expression of macrophage cholesterol efflux genes: ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) and its transcriptional regulator liver X receptor-alpha (LXRα), were significantly reduced (p<0.05) whereas expression of the classical M1 macrophage cell-surface receptor CCR2 was significantly increased (p=0.005) in the HxE -/- mice. Atherosclerotic plaque area and macrophage infiltration was significantly higher in the aortic sinus (p<0.004), and atherosclerotic lesions in the aortas were significantly higher in the HxE -/- mice (p<0.05). Conclusion: Our results suggest for the first time that Hx plays a protective role in the inflammatory properties of HDL, macrophage function and in the development of atherosclerosis in apoE-/- mice. We conclude that Hx is a novel target for the treatment of atherosclerosis.