Sex as a Profound Modifier of Atherosclerotic Lesion Development in Apolipoprotein E-deficient Mice with Different Genetic Backgrounds

Abstract

Aim: Research suggests that sex may condition atherosclerosis development against different genetic backgrounds. This study addresses the hypothesis that this effect would be exerted by changes in the different apolipoproteins present in high-density lipoproteins.
Methods: ApoE-deficient mice of both sexes with Ola 129 and C57BL/6J genetic backgrounds were fed a chow diet for 14 weeks. At the end of the dietary intervention, the development of atherosclerotic lesions, apolipoproteins, lipid metabolism, inflammation and paraoxonase were assessed.
Results: Differences between atherosclerotic lesions in Ola 129 and C57BL/6J strains of apoE-deficient mice were sex-dependent and were only statistically significant in females. Plasma levels of HDL cholesterol and apolipoproteins related to these lipoparticles, such as apoA-I, apoA-II, apoA-IV, apoA-V and apoJ, were significantly different between these two strains and there were sex-related differences in some of these apolipoproteins. Hepatic steatosis was also related to the strain and was independent of sex. In females, changes in HDL cholesterol and apolipoproteins A-I and A-II were important determinants of atherosclerosis, while this was not the case in males.
Conclusions: Our results demonstrate that atherosclerosis-related differences between Ola129 and C57BL/6J genetic backgrounds in apoE-deficient mice are sex-dependent and that this finding is explained by the differences in HDL cholesterol and its apolipoprotein components, mainly apoA-I and A-II. Overall, our findings highlight the importance of taking sex into account in the analysis of atherosclerosis and lipid metabolism in animal models.