Sex-Specific Differences of Adenosine Triphosphate Levels in Red Blood Cells Isolated From ApoE/LDLR Double-Deficient Mice

Fatih Celal Alcicek,Renata Kostogrys,Katarzyna M Marzec,Ewa Szczesny-Malysiak,Katarzyna Bulat,Jakub Dybas,Tasnim Mohaissen,Magdalena Kaczmarska,Magdalena Franczyk-Zarow

doi:10.3389/fphys.2022.839323

Abstract

In this study for the first time, we investigated the correlation between sex-specific differences in adenosine triphosphate (ATP) levels in red blood cells (RBCs) and their mechanical, biochemical, and morphological alterations during the progression of atherosclerosis in ApoE/LDLR double-deficient (ApoE/LDLR−/−) mice. Our results indicate that both sex and age affect alterations in RBCs of both ApoE/LDLR−/− and C57BL/6J mice. When compared with male RBCs, female RBCs were characterized by lower basal ATP and mean corpuscular hemoglobin concentration (MCHC), higher hemoglobin concentration (HGB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), deformability, and phosphatidylserine (PS) exposure levels, regardless of age in both, ApoE/LDLR−/− and C57BL/6J mice. ApoE/LDLR−/− mice compared with age-matched controls showed lower basal ATP levels regardless of age and sex. Intracellular ATP level of RBCs was decreased solely in senescent female C57BL/6J mice, while it was elevated in males. Basal extracellular ATP levels were 400 times lower than corresponding intracellular level. In conclusion, basal ATP levels, RBC morphology, deformability, PS exposure levels alterations are sex-dependent in mice. Changes in basal ATP levels were correlated with PS exposure and trends of changes in MCV. Trends of changes of the most RBC parameters were similar in both sexes of ApoE/LDLR−/− mice compared with age-matched controls; however, their kinetics and levels vary greatly between different stages of disease progression.

Highlights

Atherosclerosis, one of the major causes of mortality worldwide, is a disease that involves endothelial dysfunction and lipid retention in vascular intima, as the result of hyperlipidemia and lipid oxidation
Red blood cell deformability (Figure 1A) was found to be significantly decreased in ApoE/LDLR−/− mice compared with their age-matched control in both sexes
red blood cells (RBCs) isolated from male mice of both control and ApoE/LDLR−/−, were characterized by a significant decrease in deformability with age progression, contrary to RBCs acquired from females, where we did not observe any age-related differences

Summary

Introduction

Atherosclerosis, one of the major causes of mortality worldwide, is a disease that involves endothelial dysfunction and lipid retention in vascular intima, as the result of hyperlipidemia and lipid oxidation. Some of the morphological parameters of RBCs, such as hemoglobin concentration (HGB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), differ between males and females, and were previously reported to be altered to different extent in pathophysiological processes, in a sex-dependent manner (Straface et al, 2011; Kanias et al, 2016; Grau et al, 2018; Szczesny-Malysiak et al, 2021). It was previously reported that progression of atherosclerosis induces characteristic mechanical, morphological, and physiological RBC alterations (Kanakaraj and Singh, 1989; Van Zwieten et al, 2012; Unruh et al, 2015; Dybas et al, 2020), but yet, the impact of sex has not been investigated in ApoE-LDLR doubledeficient (ApoE/LDLR−/−) mice

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