Red Blood Cell Dysfunction Induced by High Fat Diet: Potential Implications for Obesity-Related Atherosclerosis
Background—High fat diet (HFD) promotes endothelial dysfunction and pro-inflammatory monocyte activation, which contribute to atherosclerosis in obesity. We investigated whether HFD also induces dysfunction of red blood cells (RBC), which serve as a reservoir for chemokines via binding to Duffy antigen receptor for chemokines (DARC).
Methods and Results—60% HFD for 12 weeks, which produced only minor changes in lipid profile in C57/BL6 mice, markedly augmented the levels of MCP-1 bound to RBC, which in turn stimulated macrophage migration through an endothelial monolayer. Levels of RBC bound KC were also increased by HFD. These effects of HFD were abolished in DARC -/- mice. In RBC from HFD-fed wild-type and DARC -/- mice, levels of membrane cholesterol and phosphatidylserine externalization were increased, fostering RBC-macrophage inflammatory interactions and promoting macrophage phagocytosis in vitro. When labeled ex vivo and injected into control mice, RBC from HFD-fed mice exhibited ~3 fold increase in splenic uptake. Finally, RBC from HFD-fed mice induced increased macrophage adhesion to the endothelium when they were incubated with isolated aortic segments, indicating endothelial activation.
Conclusions—RBC dysfunction, analogous to endothelial dysfunction, occurs early during diet-induced obesity and may serve as a mediator of atherosclerosis. These findings may have implications for the pathogenesis of atherosclerosis in obesity, a worldwide epidemic.
- Received May 1, 2015.
- Revision received August 5, 2015.
- Accepted August 28, 2015.