Andreas M. Beyer, Julie K. Freed, Matthew J. Durand, Michael Riedel, Karima Ait-Aissa, Paula Green, Joseph C. Hockenberry, R. Garret Morgan, Anthony J. Donato, Refael Peleg, Mario Gasparri, Chris K. Rokkas, Janine H. Santos, Esther Priel, David D. Gutterman
Rationale : Telomerase is a nuclear regulator of telomere elongation with recent reports suggesting a role in regulation of mitochondrial reactive oxygen species. Flow-mediated dilation in patients with cardiovascular disease is dependent on the formation of reactive oxygen species.
Objective : We examined the hypothesis that telomerase activity modulates microvascular ow-mediated dilation, and loss of telomerase activity contributes to the change of mediator from nitric oxide to mitochondrial hydrogen peroxide in patients with coronary artery disease (CAD).
Methods and Results : Human coronary and adipose arterioles were isolated for videomicroscopy. Flow-mediated dilation was measured in vessels pretreated with the telomerase inhibitor BIBR-1532 or vehicle. Statistical differences between groups were determined using a 2-way analysis of variance repeated measure (n≥4; P<0.05). L-NAME (Nω-nitro-L-arginine methyl ester; nitric oxide synthase inhibitor) abolished ow-mediated dilation in arterioles from subjects without CAD, whereas polyethylene glycol-catalase (PEG-catalase; hydrogen peroxide scavenger) had no effect. After exposure to BIBR-1532, arterioles from non-CAD subjects maintained the magnitude of dilation but changed the mediator from nitric oxide to mitochondrial hydrogen peroxide (% max diameter at 100 cm H2O: vehicle 74.6±4.1, L-NAME 37.0±2.0*, PEG-catalase 82.1±2.8; BIBR-1532 69.9±4.0, L-NAME 84.7±2.2, PEG-catalase 36.5±6.9*). Conversely, treatment of microvessels from CAD patients with the telomerase activator AGS 499 converted the PEG-catalase-inhibitable dilation to one mediated by nitric oxide (% max diameter at 100 cm H2O: adipose, AGS 499 78.5±3.9; L-NAME 10.9±17.5*; PEG-catalase 79.2±4.9). Endothelial-independent dilation was not altered with either treatment.
Conclusions : We have identi ed a novel role for telomerase in re-establishing a physiological mechanism of vasodilation in arterioles from subjects with CAD. These ndings suggest a new target for reducing the oxidative milieu in the microvasculature of patients with CAD.
(Circ Res. 2016;118:856-866. DOI: 10.1161/ CIRCRESAHA.115.307918.)
Key Words : coronary artery disease ■ ow-mediated dilation ■ microvascular dysfunction ■ mitochondria ■ reactive oxygen species ■ telomerase activity ■ vascular biology