Red blood cell dysfunction induced by high-fat diet: Potential implications for obesity-related atherosclerosis

Dusten Unruh, Ramprasad Srinivasan, Tyler Benson, Stephen Haigh, Danielle Coyle, Neil Batra, Ryan Keil, Robert Sturm, Victor Blanco, Mary Palascak, Robert S. Franco, Wilson Tong, Tapan Chatterjee, David Y. Hui, W. Sean Davidson, Bruce J. Aronow, Theodosia Kalfa, David Manka, Abigail Peairs, Andra BlomkalnsDavid J. Fulton, Julia E. Brittain, Neal L. Weintraub, Vladimir Y. Bogdanov

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Background - High-fat diet (HFD) promotes endothelial dysfunction and proinflammatory monocyte activation, which contribute to atherosclerosis in obesity. We investigated whether HFD also induces the dysfunction of red blood cells (RBCs), which serve as a reservoir for chemokines via binding to Duffy antigen receptor for chemokines (DARC). Methods and Results - A 60% HFD for 12 weeks, which produced only minor changes in lipid profile in C57/BL6 mice, markedly augmented the levels of monocyte chemoattractant protein-1 bound to RBCs, 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 RBCs 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 wild-type mice, RBCs from HFD-fed mice exhibited ≈3-fold increase in splenic uptake. Finally, RBCs 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.

Original languageEnglish (US)
Pages (from-to)1898-1908
Number of pages11
JournalCirculation
Volume132
Issue number20
DOIs
StatePublished - Nov 17 2015

Keywords

  • atherosclerosis
  • erythrocytes
  • leukocytes
  • obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Unruh, D., Srinivasan, R., Benson, T., Haigh, S., Coyle, D., Batra, N., Keil, R., Sturm, R., Blanco, V., Palascak, M., Franco, R. S., Tong, W., Chatterjee, T., Hui, D. Y., Davidson, W. S., Aronow, B. J., Kalfa, T., Manka, D., Peairs, A., ... Bogdanov, V. Y. (2015). Red blood cell dysfunction induced by high-fat diet: Potential implications for obesity-related atherosclerosis. Circulation, 132(20), 1898-1908. https://doi.org/10.1161/CIRCULATIONAHA.115.017313