Age-dependent accumulation of mitochondrial DNA deletions in the aortic root of atherosclerosis-prone apolipoprotein E-knockout mice.

Purpose: To investigate whether mitochondrial DNA (mtDNA) damage, specifically deletion, contributes to the development of atherosclerosis or is simply a secondary effect of the primary factors causing atherosclerosis.

Materials And Methods: mtDNA deletion was detected by PCR in the aortic root of atherosclerosis-prone C57BL/6J apolipoprotein (Apo) E gene deficient (-/-) mice and control C57BL/6J mice at different ages. Atherosclerotic plaques in the Apo E-/- mice were assessed using frozen sections of the aortic root. The protein levels of COX III and 8-oxoguanine glycosylase (OGG1) were determined.

Results: while mtDNA deletions accumulated significantly in mice as young as 2- month-old, atherosclerotic plaques were not detected until mice were 6 months old or older, suggesting that mtDNA deletion occurs prior to the formation of atherosclerotic plaques in the aortic root of these mice. Moreover, the expression levels of mtDNA-encoded COX III protein in both 2-month-old and 16-month-old C57BL/6J ApoE-/- mice were significantly lower than those in C57BL/6J mice (p<0.05). Additionally, the protein level of 8-oxoguanine glycosylase (OGG1), a mitochondrial enzyme that functions in DNA excision repair, decreased with age in these mice, indicating that age-related down-regulation of mtDNA excision repair also contributes to atherosclerosis in C57BL/6J ApoE-/- mice.

Conclusion: These results reveal that mtDNA deletions occur during the early "initiation" stage of atherosclerosis in C57BL/6J ApoE-/- mice and have the potential to promote atherosclerosis.