Apolipoprotein A-I protection against atherosclerosis is dependent on genetic background

Timothy J Sontag, Paulette A Krishack, John R Lukens, Clarissa V Bhanvadia, Godfrey S Getz, Catherine A Reardon
Arteriosclerosis, Thrombosis, and Vascular Biology 2014, 34 (2): 262-9

OBJECTIVE: Inbred mouse strains have different susceptibilities to experimental atherosclerosis. The C57BL/6 strain is among the most sensitive and has, therefore, been the most widely used in atherosclerosis studies, whereas many strains are resistant. The FVB/N strain is highly resistant to atherosclerosis on the apolipoprotein E (apoE)- and low-density lipoprotein (LDL) receptor-deficient backgrounds. High-density lipoprotein and its major apoprotein, apoA-I, have been shown to be protective against atherogenesis on the C57BL/6 background. We here examine the influence of genetic background on the atheroprotective nature of apoA-I.

APPROACH AND RESULTS: ApoE-deficient/apoA-I-deficient mice were generated in the C57BL/6 and FVB/N strains from apoE-deficient mice. After 6 to 10 weeks on a Western-type diet, plasma lipids and atherosclerotic lesion size were assessed. Macrophage recruitment, cholesterol regulation, and blood monocyte levels were examined as potential mechanisms driving lesion size differences. FVB/N knockout mice had higher plasma very-LDL/LDL cholesterol than their C57BL/6 counterparts. ApoA-I deficiency decreased very-LDL/LDL cholesterol in C57BL/6 mice but not in FVB/N mice. FVB/N single and double knockout mice had less lesion than C57BL/6 6 to 10 weeks on diet. ApoA-I deficiency augmented lesion development only in C57BL/6 mice. Macrophage recruitment to thioglycollate-treated peritoneum and diet-induced blood monocyte levels reflected the pattern of lesion development among the 4 genotypes. ApoA-I deficiency increased macrophage cholesterol content only in C57BL/6. FVB/N plasma was a better acceptor for macrophage cholesterol efflux than C57BL/6.

CONCLUSIONS: ApoA-I is atheroprotective only in certain genetic contexts. In the C57BL/6 context, but not FVB/N, apoA-I decreases inflammatory macrophage recruitment and monocytosis, contributors to lesion formation.

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