Abstract 14990: Hemopexin Improves High Density Lipoprotein Function and Inhibits the Development of Atherosclerosis in apoE Null Mice
Introduction: The inverse relationship between high density lipoprotein-cholesterol (HDL-C) and the risk of atherosclerosis is well established. Although HDL-C is an epidemiological predictor of the risk for coronary heart disease (CHD), a significant number of CHD events occur in patients with normal LDL and HDL cholesterol levels. Recent studies have demonstrated that the anti- or pro-inflammatory nature of HDL may be a more sensitive indicator of atherosclerosis than HDL-C levels alone. However, the mechanisms that are regulating the inflammatory nature of HDL are unknown.
Hypothesis: In a proteomics study, we discovered that under atherogenic conditions hemoglobin (Hb) and its scavenger proteins haptoglobin (Hp) and hemopexin (Hx) are significantly increased and associated with pro-inflammatory HDL in both mice and man. Since Hx plays an important anti-inflammatory role by mitigating the oxidative damage of heme during an acute phase response, we hypothesized that Hx association with pro-inflammatory HDL may play a role in inflammatory properties of HDL and the subsequent development of atherosclerosis.
Methods: We obtained mice that are deficient for Hx and bred them on to the hyperlipidemic apoE null background to generate the double knockout; HxE-/- mice. Twenty four week old female HxE-/- mice and apoE-/- mice (n=15-20 per group, fed a chow diet) were sacrificed and analyzed for lipid profiles and atherosclerosis.
Results: Lipoprotein profiles were not significantly different between the two groups of mice; however, there was a significant increase in free fatty acids in HxE-/- mice compared to apoE-/- mice (p<0.001). HxE-/- mice demonstrated a significant increase in atherosclerosis in the aortic sinus compared to apoE-/- mice (p<0.001) and macrophage content was higher in HxE-/- mice (p<0.004). En face analysis revealed significantly more atherosclerotic lesions in the aortas of HxE-/- mice compared to apoE-/- mice. Furthermore, in ex vivo assays, HDL from HxE-/- mice was significantly more inflammatory (p<0.002) compared to HDL from apoE-/- mice.
Conclusion: Our results suggest for the first time that Hx plays an important role in both the inflammatory properties of HDL and the development of atherosclerosis in apoE null mice.
- © 2013 by American Heart Association, Inc.