Apolipoprotein E−/− Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function
Objective—We previously reported that hemopexin (Hx), a heme scavenger, is significantly increased and associated with proinflammatory high-density lipoprotein under atherogenic conditions. Although it is established that Hx together with macrophages plays a role in mitigating oxidative damage, the role of Hx in the development of atherosclerosis is unknown.
Approach and Results—We used Hx and apoE double-knockout mice (HxE−/−) to determine the role of Hx in the development of atherosclerosis. HxE−/− mice had significantly more free heme, reactive oxygen species, and proinflammatory high-density lipoprotein in their circulation, when compared with control apoE−/− mice. Atherosclerotic plaque area (apoE−/−=9.72±2.5×104 μm2 and HxE−/−=27.23±3.6×104 μm2) and macrophage infiltration (apoE−/−=38.8±5.8×103 μm2 and HxE−/−=103.4±17.8×103 μm2) in the aortic sinus were significantly higher in the HxE−/− mice. Atherosclerotic lesions in the aortas were significantly higher in the HxE−/− mice compared with apoE−/− mice. Analysis of polarization revealed that macrophages from HxE−/− mice were more M1-like. Ex vivo studies demonstrated that HxE−/− macrophage cholesterol efflux capacity was significantly reduced when compared with apoE−/− mice. Injection of human Hx into HxE−/− mice reduced circulating heme levels and human Hx pretreatment of naive bone marrow cells ex vivo resulted in a shift from M1- to M2-like macrophages.
Conclusions—We conclude that Hx plays a novel protective role in alleviating heme-induced oxidative stress, improving inflammatory properties of high-density lipoprotein, macrophage phenotype and function, and inhibiting the development of atherosclerosis in apoE−/− mice.
- Received June 19, 2015.
- Accepted March 31, 2016.
- © 2016 American Heart Association, Inc.