Abstract
ObjectivePrior studies demonstrate mitochondrial dysfunction with increased reactive oxygen species generation in peripheral blood mononuclear cells in diabetes mellitus. Oxidative stress-mediated damage to mitochondrial DNA promotes atherosclerosis in animal models. Thus, we evaluated the relation of mitochondrial DNA damage in peripheral blood mononuclear cells s with vascular function in patients with diabetes mellitus and with atherosclerotic cardiovascular disease.Approach and resultsWe assessed non-invasive vascular function and mitochondrial DNA damage in 275 patients (age 57 ± 9 years, 60 % women) with atherosclerotic cardiovascular disease alone (N = 55), diabetes mellitus alone (N = 74), combined atherosclerotic cardiovascular disease and diabetes mellitus (N = 48), and controls age >45 without diabetes mellitus or atherosclerotic cardiovascular disease (N = 98). Mitochondrial DNA damage measured by quantitative PCR in peripheral blood mononuclear cells was higher with clinical atherosclerosis alone (0.55 ± 0.65), diabetes mellitus alone (0.65 ± 1.0), and combined clinical atherosclerosis and diabetes mellitus (0.89 ± 1.32) as compared to control subjects (0.23 ± 0.64, P < 0.0001). In multivariable models adjusting for age, sex, and relevant cardiovascular risk factors, clinical atherosclerosis and diabetes mellitus remained associated with higher mitochondrial DNA damage levels (β = 0.14 ± 0.13, P = 0.04 and β = 0.21 ± 0.13, P = 0.002, respectively). Higher mitochondrial DNA damage was associated with higher baseline pulse amplitude, a measure of arterial pulsatility, but not with flow-mediated dilation or hyperemic response, measures of vasodilator function.ConclusionsWe found greater mitochondrial DNA damage in patients with diabetes mellitus and clinical atherosclerosis. The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.
Highlights
Type 2 diabetes mellitus affects an estimated 1 in 10 Americans and this number is expected climb with the current obesity epidemic [1]
The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact
Atherosclerosis alone or in the presence of diabetes mellitus was associated with higher burden of cardiovascular risk factors
Summary
Type 2 diabetes mellitus affects an estimated 1 in 10 Americans and this number is expected climb with the current obesity epidemic [1]. Diabetes mellitus is a Mitochondrial DNA is more susceptible to oxidative damage compared to nuclear DNA due to multiple. Mitochondrial DNA damage has been closely associated with dysfunctional oxidative phosphorylation, which leads to further oxidative stress resulting in a positive-feedback cycle. In a prior human study of patients with coronary artery disease, the extent of mitochondrial DNA damage in circulating white cells was associated with high risk plaque burden [12]. We have previously described altered mitochondrial oxidative phosphorylation, membrane potential and morphology in peripheral blood mononuclear cells which was associated with vascular dysfunction in patients with diabetes [7, 13]. The objective of the present study was to assess the relation of mitochondrial DNA damage in peripheral blood mononuclear cells to vascular function and the presence of diabetes mellitus and atherosclerotic cardiovascular disease
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