Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation

Abstract

Not all of the effects of telomerase can be easily explained by its nuclear actions. Growing evidence suggests that TERT, the catalytic subunit of telomerase, can reversibly translocate from the nucleus to organelles (including the mitochondria), in a dose-and time-dependent manner, in response to stressors, Objective: We examined the hypothesis that telomerase activity modulates microvascular flow-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). Clinical Track 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 (N ω -nitro-L-arginine methyl ester; nitric oxide synthase inhibitor) abolished flow-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 H 2 O: 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 H 2 O: 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:

Thirty Years of Saying NO

“…The same is true for selective deletion of endothelial SOD, which leads to increased oxidative stress and reduced endotheliumdependent, NO-mediated relaxations. The exaggerated reduction in NO bioavailability caused by ROS can be alleviated experimentally by (1) inhibiting the activation of endothelial cell membrane transforming growth factor-β 154 and endoplasmic reticulum membrane TLR9 receptors 155 thereby reducing the expression of NOX and cyclooxygenase-2; (2) augmenting (eg, with the administration of adiponectin, capsaicin, or glucagon-like peptide-1; see Other Hormones and Circulating Mediators section of this article) the intracellular concentration of cAMP to activate PKA that increases uncoupling protein 2 in the mitochondria and cAMP-responsive element-binding protein in the nucleus, boosting the expression of the antioxidant enzymes mitochondrial complex I and HO-1, respectively; (3) stimulating AMPK (eg, by augmenting the production of adiponectin) to activate nuclear factor-erythroid 2-related factor-2 and thus stimulates HO-1 gene transcription; (4) reducing ROS production and DNA release in the mitochondria (by activating telomerase and increasing the presence of its catalytic subunit 156 ); and (5) by the exogenous administration of epigallocatechins, 157 erythropoietin, 112 ghrelin, 158 estrogens, 89 or other antioxidants. 15,92,120 Part of the improvement of endothelium-dependent relaxations caused by HO-1 induction or exogenous antioxidants can be attributed to restoration of the gatekeeper role of NO in preventing endothelium-dependent contractions.…”

Telomeres and Telomerase in The Aging Heart

“…Many studies have also demonstrated that acute activation of telomerase using AGS-499 restored NO bioavailability and limited ROS production in micro-vessels from subjects with CAD. (153) …”

The Secret Life of Telomerase

“…In the current issue of Circulation Research, Beyer et al 7 build on this conceptual thread pursuing a unique line of inquiry in the resistance vasculature. Could telomerase, or more specifically TERT, regulate arterial tone by localizing to mitochondria and influencing the production of reactive oxygen species?…”