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

Abstract

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.

• Authors: Timothy J Sontag, Paulette A Krishack, John R Lukens, Clarissa V Bhanvadia, Godfrey S Getz, Catherine A Reardon
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 34 Issue 2 Pg. 262-9 (Feb 2014) ISSN: 1524-4636 [Electronic] United States
• PMID: 24334873 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• Apolipoproteins E
• Triglycerides
• Cholesterol

Topics

• Animals
• Aorta (metabolism, pathology)
• Aortic Diseases (genetics, metabolism, pathology, prevention & control)
• Apolipoprotein A-I (deficiency, genetics, metabolism)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (genetics, metabolism, pathology, prevention & control)
• Brachiocephalic Trunk (metabolism, pathology)
• Cell Line
• Cholesterol (blood)
• Disease Models, Animal
• Female
• Genetic Predisposition to Disease
• Macrophages (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (metabolism, pathology)
• Species Specificity
• Time Factors
• Triglycerides (blood)