Abstract
Rational: Heart disease is the leading cause of death worldwide and abnormalities in mitochondrial function are increasingly recognized in association with cardiomyopathy, heart failure, endothelial dysfunction and coronary artery disease (CAD). However the direct contribution and mechanism of the mitochondrial dysfunction on the development of CAD is not fully determined. We have recently shown a critical role of TERT, the catalytic subunit of telomerase, as a regulator of mitochondrial integrity in the microcirculation. We observed increased expression of the dominant negative splice variant of TERT ( β -del) in the Left Ventricle from subjects with CAD. Therefore, we hypothesize that TERT ( β -del) decreases mitochondrial telomerase activity in the human heart resulting in mitochondrial damage that contributes to an environment that promotes the development of CAD . Methods: Fresh and frozen tissue samples of discarded heart tissue from subjects with and without CAD were used. Protein, cell lysate or mitochondria were isolated using standard techniques. Mitochondrial DNA, levels of NAD+ and ATP as well as mitochondrial oxidative phosphorylation were evaluated. Results: PCR analysis revealed an increased frequency of mitochondrial common deletion, an established marker for mitochondrial abnormalities (0.9±0.2 in CAD; vs 1.5±0.2 in non-CAD; N=8; P<0.05). NAD+ and ATP levels were significantly decreased in CAD subjects compared to non-CAD (291±62 and 0.5±0.1 RLU/mg protein in CAD vs. 4203±336 and 84.1±24.8 pmol/mg protein in non-CAD respectively; N=15; P<0.005). Decrease respiration control index (RCI) in the presence of either complex I substrate K (+)-pyruvate/malate (PM) or complex II substrate K (+)-succinate (SUC) was observed in tissue form subjects with CAD (KPM-RCI: 2.9±1.3; SUC-RCI: 7.6± 1.9 in CAD vs KPM-RCI: 8.5±1.9; SUC-RCI: 19.1± 8.3 in non-CAD; N=3; P<0.05) Conclusions: Together these results point to significantly impaired mitochondrial function in subjects with CAD that are associated with decreased in mitochondrial telomerase activity.
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