Heterozygous transferrin receptor 1 deletion reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice.

BACKGROUND: Transferrin receptor 1 (TfR1), an intracellular iron receptor, has multiple biological functions. We have previously reported that aortic TfR1 expression increases in human and murine abdominal aortic aneurysm, but its role in the development of atherosclerosis remains unclear. In the present study, we generated apolipoprotein-E (ApoE) and TfR1 deficient mice and examined the impact of its deletion on the development of atherosclerosis. METHODS AND RESULTS: Homozygous ApoE deficient (ApoE (-/-) ) mice were crossbred to heterozygous TfR1 deficient (TfR1 (+/-) ) mice to generate ApoE and TfR1 deficient (ApoE (-/-) /TfR1 (+/-) ) mice. ApoE (-/-) and ApoE (-/-) /TfR1 (+/-) mice presented a similar phenotype including body weight and lipid values. Of note, after a high-fat feeding for 16 weeks, ApoE (-/-) /TfR1 (+/-) mice exhibited a reduction of the atherosclerotic areas in the aortic sinus and aorta compared with ApoE (-/-) mice despite similar lipid values. In addition, ApoE (-/-) /TfR1 (+/-) mice showed decreases in oxidative stress and macrophage accumulation in the aortic sinus and aorta compared with ApoE (-/-) mice. CONCLUSIONS: These results indicate that TfR1 deletion attenuates the development of atherosclerotic lesion formation in ApoE (-/-) mice.