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Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction. Am J Physiol Heart Circ Physiol 2018 05 01;314(5):H1053-H1060

Date

01/20/2018

Pubmed ID

29351466

Pubmed Central ID

PMC6008150

DOI

10.1152/ajpheart.00472.2017

Scopus ID

2-s2.0-85046904084   16 Citations

Abstract

A rise in reactive oxygen species (ROS) may contribute to cardiovascular disease by reducing nitric oxide (NO) levels, leading to loss of NO's vasodilator and anti-inflammatory effects. Although primarily studied in larger conduit arteries, excess ROS release and a corresponding loss of NO also occur in smaller resistance arteries of the microcirculation, but the underlying mechanisms and therapeutic targets have not been fully characterized. We examined whether either of the two subunits of telomerase, telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC), affect microvascular ROS production and peak vasodilation at baseline and in response to in vivo administration to angiotensin II (ANG II). We report that genetic loss of TERT [maximal dilation: 52.0 ± 6.1% with vehicle, 60.4 ± 12.9% with Nω-nitro-l-arginine methyl ester (l-NAME), and 32.2 ± 12.2% with polyethylene glycol-catalase (PEG-Cat) ( P < 0.05), means ± SD, n = 9-19] but not TERC [maximal dilation: 79 ± 5% with vehicle, 10.7 ± 9.8% with l-NAME ( P < 0.05), and 86.4 ± 8.4% with PEG-Cat, n = 4-7] promotes flow-induced ROS formation. Moreover, TERT knockout exacerbates the microvascular dysfunction resulting from in vivo ANG II treatment, whereas TERT overexpression is protective [maximal dilation: 88.22 ± 4.6% with vehicle vs. 74.0 ± 7.3% with ANG II (1,000 ng·kg-1·min-1) ( P = not significant), n = 4]. Therefore, loss of TERT but not TERC may be a key contributor to the elevated microvascular ROS levels and reduced peak dilation observed in several cardiovascular disease pathologies. NEW & NOTEWORTHY This study identifies telomerase reverse transcriptase (TERT) but not telomerase RNA component as a key factor regulating endothelium-dependent dilation in the microcirculation. Loss of TERT activity leads to microvascular dysfunction but not conduit vessel dysfunction in first-generation mice. In contrast, TERT is protective in the microcirculation in the presence of prolonged vascular stress. Understanding the mechanism of how TERT protects against vascular stress represents a novel target for the treatment of vascular disorders.

Author List

Ait-Aissa K, Kadlec AO, Hockenberry J, Gutterman DD, Beyer AM

Authors

Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of Wisconsin
David D. Gutterman MD Sr Associate Director, Professor in the Medicine department at Medical College of Wisconsin




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

Angiotensin II
Animals
Coronary Vessels
Endothelium, Vascular
Female
Hydrogen Peroxide
Male
Mesenteric Arteries
Mice, Inbred C57BL
Mice, Knockout
Microvessels
Nitric Oxide
RNA
Telomerase
Vasodilation