Abstract 17482: Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species and Correlates With Higher Risk Plaques in Humans
Mitochondrial DNA (mtDNA) damage occurs in both the vessel wall and in circulating cells in human atherosclerosis. However, whether mtDNA damage promotes atherogenesis or is a consequence of tissue damage is unknown. We assessed the hypothesis that mtDNA damage can directly promote atherosclerosis and affect plaque composition.
We compared apolipoprotein E deficient mice, which were also deficient for mtDNA polymerase γ proof reading activity (PolG-/-/ApoE-/-) with control mice (PolG+/+/ApoE-/-) (n=12). The mice were assessed for levels of atherosclerosis, mtDNA damage, mitochondrial dysfunction and reactive oxygen species (ROS). We characterized phenotypic changes in vascular smooth muscle cells (VSMCs) and monocytes. To understand the clinical importance of mtDNA damage, we examined whether leukocyte mtDNA damage correlated with atherosclerosis extent or plaque vulnerability. QPCR analysis was performed on leukocytes from patients (n=170) who had undergone virtual histology intravascular ultrasound characterisation of coronary plaques.
PolG-/-/ApoE-/- mice showed extensive mtDNA damage, impaired mitochondrial respiration and increased atherosclerosis (38±2.8% vs 30.3±1.9%) in the absence of increased ROS. PolG-/-/ApoE-/- VSMCs had decreased oxygen consumption rate and reduced ATP content (0.19±0.04 vs 2.74±0.6 nmoles), despite an increased in basal glycolysis. The bioenergetic impairment altered the VSMC phenotype, reducing proliferation and increasing apoptosis. Furthermore polG-/-/ApoE-/- monocytes showed increased inflammatory cytokine release, without increased ROS, and transplantation with polG-/-/ApoE-/- bone marrow induced plaque vulnerability. Consistent with these findings, leukocyte mtDNA damage in humans was associated with thin cap fibroatheromas (p=0.013)- the lesions with the highest risk of cardiovascular events on subsequent follow up.
In conclusion mtDNA defects promote atherosclerosis and plaque vulnerability, independently of ROS, through effects on VSMCs and monocytes. Protection against mtDNA damage, and improvement of mitochondrial function, are potential areas for new therapeutics. Biomarkers of mtDNA damage also show promise to risk-stratify CAD patients.
- © 2013 by American Heart Association, Inc.