Abstract 19720: Accumulation of Mitochondrial DNA Mutations Leads to Endothelial Dysfunction
Aging is associated with endothelial dysfunction which leads to decreased vascular reactivity and increased risk of cardiovascular events. Mitochondrial DNA (mtDNA) mutations also increase with aging. However, the possible link between endothelial dysfunction and mtDNA mutations remains unclear. We tested the hypothesis that accumulation of mtDNA mutations would increase reactive oxygen species (ROS) production, decrease endothelial nitric oxide synthase (eNOS) and thus reduce NO bioavailability resulting in endothelial dysfunction. To test this hypothesis we used a mouse model of premature aging previously generated through knock-in of a proof-reading defective mtDNA polymerase (mtmut mice), which accumulate increased mtDNA mutations. 16-week old mtmut mice and wild-type (WT) littermates were subjected to hind limb ischemia (HLI) and flow recovery followed by laser doppler imaging. Vascular reactivity was assessed by measuring blood flow after regional heating (5 min, 42°C) and after arterial occlusion (5 min). Mtmut mice exhibited impaired recovery of blood flow after HLI as compared to WT littermates (54% vs 79% by 7 days, respectively, p=0.045). Vascular reactivity was also lower in the mtmut mice compared to WT both after heating (4%±2 increase in perfusion vs 23%±10 in WT, p=0.02) and arterial occlusion (1%±1 in mtmut mice vs 25%±6 in WT, p=0.002). Mtmut mice also had reduced levels of eNOS and decreased eNOS Ser1177 phosphorylation in endothelial cells as shown by western blot. Preliminary results also suggest ROS production in isolated mtmut endothelial cells was not different at baseline but was increased compared to WT after hypoxia-reoxygenation as measured by fluorogenic marker carboxy-H2DCFDA.
Conclusion: Accumulation of mtDNA mutations is sufficient to cause endothelial dysfunction, likely through increased ROS production, decreased levels of eNOS and reduced NO bioavailability. This could contribute to impaired collateral formation and recovery from ischemia in elderly patients.
- © 2010 by American Heart Association, Inc.