TY - JOUR
T1 - Red blood cell dysfunction induced by high-fat diet
T2 - Potential implications for obesity-related atherosclerosis
AU - Unruh, Dusten
AU - Srinivasan, Ramprasad
AU - Benson, Tyler
AU - Haigh, Stephen
AU - Coyle, Danielle
AU - Batra, Neil
AU - Keil, Ryan
AU - Sturm, Robert
AU - Blanco, Victor
AU - Palascak, Mary
AU - Franco, Robert S.
AU - Tong, Wilson
AU - Chatterjee, Tapan Kumar
AU - Hui, David Y.
AU - Davidson, W. Sean
AU - Aronow, Bruce J.
AU - Kalfa, Theodosia
AU - Manka, David
AU - Peairs, Abigail
AU - Blomkalns, Andra
AU - Fulton, David J.
AU - Brittain, Julia Elizabeth
AU - Weintraub, Neal L.
AU - Bogdanov, Vladimir Y.
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/11/17
Y1 - 2015/11/17
N2 - 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.
AB - 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.
KW - atherosclerosis
KW - erythrocytes
KW - leukocytes
KW - obesity
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U2 - 10.1161/CIRCULATIONAHA.115.017313
DO - 10.1161/CIRCULATIONAHA.115.017313
M3 - Article
C2 - 26467254
AN - SCOPUS:84947485313
SN - 0009-7322
VL - 132
SP - 1898
EP - 1908
JO - Circulation
JF - Circulation
IS - 20
ER -