Age–related and atherosclerosis–related erythropathy in ApoE/LDLR−/− mice

Abstract

In this work we applied a multimodal approach to define the age– and atherosclerosis–related biochemical and functional alterations in red blood cells (RBCs) in ApoE/LDLR−/− mice. Our results revealed that age–related changes in RBCs, such as decreases in RBC deformability and mean height, were more pronounced in ApoE/LDLR−/− mice than in age–matched control mice (C57BL/6J). The decreases in phospholipid content and level of lipid unsaturation were accompanied by an increase in cholesterol esters and esterified lipids in RBC membranes in aged C57BL/6J mice. The age–related decrease in the phospholipid content was more pronounced in ApoE/LDLR−/− mice. In contrast, the increase in the total lipid content in RBC membranes occurred only in ApoE/LDLR−/− mice with advanced atherosclerosis. The age–related alterations also included a decrease in the ratio of turns to α–helices in the secondary structure of hemoglobin (Hb) inside intact RBCs. On the other hand, an increase in the ratio of unordered conformations to α–helices of Hb was observed only in ApoE/LDLR−/− mice and occurred already at the age of 5–weeks. This was related to hypercholesterolemia and resulted in an increased oxygen-carrying capacity. In conclusion, progressive mechanical and functional alterations of RBCs in aged ApoE/LDLR−/− mice were more pronounced than in age–matched C57BL/6J mice. Although, several biochemical changes in RBCs in aged ApoE/LDLR−/− mice recapitulated age–dependent changes observed in control mice, some biochemical features of RBC membranes attributed to hypercholesterolemia were distinct and could contribute to the accelerated deterioration of RBC function in ApoE/LDLR−/− mice.