Journal article
Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation
Circulation research, Vol.118(5), pp.856-866
03/04/2016
DOI: 10.1161/CIRCRESAHA.115.307918
PMCID: PMC4772813
PMID: 26699654
Abstract
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.
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).
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 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.
We have identified a novel role for telomerase in re-establishing a physiological mechanism of vasodilation in arterioles from subjects with CAD. These findings suggest a new target for reducing the oxidative milieu in the microvasculature of patients with CAD.
Details
- Title: Subtitle
- Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation
- Creators
- Andreas M Beyer - Medical College of WisconsinJulie K Freed - Medical College of WisconsinMatthew J Durand - Medical College of WisconsinMichael Riedel - Medical College of WisconsinKarima Ait-Aissa - Medical College of WisconsinPaula Green - Rutgers, The State University of New JerseyJoseph C Hockenberry - Medical College of WisconsinR Garret Morgan - University of UtahAnthony J Donato - University of UtahRefael Peleg - Ben-Gurion University of the NegevMario Gasparri - Medical College of WisconsinChris K Rokkas - Medical College of WisconsinJanine H Santos - National Institute of Environmental Health SciencesEsther Priel - Ben-Gurion University of the NegevDavid D Gutterman - Medical College of Wisconsin
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.118(5), pp.856-866
- DOI
- 10.1161/CIRCRESAHA.115.307918
- PMID
- 26699654
- PMCID
- PMC4772813
- NLM abbreviation
- Circ Res
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- R01 HL113612 / NHLBI NIH HHS K02 AG045339 / NIA NIH HHS T32HL007792 / NHLBI NIH HHS R01 HL135901 / NHLBI NIH HHS R21 AG043952 / NIA NIH HHS R01 AG040297 / NIA NIH HHS T32 GM089586 / NIGMS NIH HHS R21 AG0443952 / NIA NIH HHS R21 OD018306 / NIH HHS GM089586 / NIGMS NIH HHS P01 HL068769 / NHLBI NIH HHS
- Language
- English
- Date published
- 03/04/2016
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984360155502771
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