Faculty Collaboration Database

Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation. Circ Res 2016 Mar 04;118(5):856-66

Date

12/25/2015

Pubmed ID

26699654

Pubmed Central ID

PMC4772813

DOI

10.1161/CIRCRESAHA.115.307918

Scopus ID

2-s2.0-84952008563 (requires institutional sign-in at Scopus site)   83 Citations

Abstract

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 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).

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 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 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.

Author List

Beyer AM, Freed JK, Durand MJ, Riedel M, Ait-Aissa K, Green P, Hockenberry JC, Morgan RG, Donato AJ, Peleg R, Gasparri M, Rokkas CK, Santos JH, Priel E, Gutterman DD

Authors

Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Matt Durand PhD Associate Professor in the Physical Medicine and Rehabilitation department at Medical College of Wisconsin
Julie K. Freed MD, PhD Vice Chair, Associate Professor in the Anesthesiology department at Medical College of Wisconsin
Mario G. Gasparri MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adipose Tissue
Aged
Arterioles
Blood Flow Velocity
Cells, Cultured
Coronary Artery Disease
Coronary Vessels
Endothelium, Vascular
Female
Human Umbilical Vein Endothelial Cells
Humans
Male
Microcirculation
Middle Aged
Telomerase
Vasodilation