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Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction
Journal article   Open access   Peer reviewed

Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction

Karima Ait-Aissa, Andrew O Kadlec, Joseph Hockenberry, David D Gutterman and Andreas M Beyer
American journal of physiology. Heart and circulatory physiology, Vol.314(5), pp.H1053-H1060
05/01/2018
DOI: 10.1152/ajpheart.00472.2017
PMCID: PMC6008150
PMID: 29351466
url
https://doi.org/10.1152/ajpheart.00472.2017View
Published (Version of record) Open Access

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 N -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 ·min ) ( 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.
 Angiotensin II - toxicity Animals Coronary Vessels - drug effects Coronary Vessels - enzymology Coronary Vessels - physiopathology Endothelium, Vascular - drug effects Endothelium, Vascular - enzymology Endothelium, Vascular - physiopathology Female Hydrogen Peroxide - metabolism Male Mesenteric Arteries - drug effects Mesenteric Arteries - enzymology Mesenteric Arteries - physiopathology Mice, Inbred C57BL Mice, Knockout Microvessels - drug effects Microvessels - enzymology Microvessels - physiopathology Nitric Oxide - metabolism RNA - genetics RNA - metabolism Telomerase - deficiency Telomerase - genetics Telomerase - metabolism Vasodilation - drug effects

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