Faculty Collaboration Database

Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease. Function (Oxf) 2022;3(5):zqac043

Date

09/29/2022

Pubmed ID

36168588

Pubmed Central ID

PMC9508843

DOI

10.1093/function/zqac043

Scopus ID

2-s2.0-85140334290 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

Telomerase reverse transcriptase (TERT) (catalytic subunit of telomerase) is linked to the development of coronary artery disease (CAD); however, whether the role of nuclear vs. mitchondrial actions of TERT is involved is not determined. Dominant-negative TERT splice variants contribute to decreased mitochondrial integrity and promote elevated reactive oxygen species production. We hypothesize that a decrease in mitochondrial TERT would increase _mtDNA damage, promoting a pro-oxidative redox environment. The goal of this study is to define whether mitochondrial TERT is sufficient to maintain nitric oxide as the underlying mechanism of flow-mediated dilation by preserving _mtDNA integrity.Immunoblots and quantitative polymerase chain reaction were used to show elevated levels of splice variants α- and β-deletion TERT tissue from subjects with and without CAD. Genetic, pharmacological, and molecular tools were used to manipulate TERT localization. Isolated vessel preparations and fluorescence-based quantification of _mtH₂O₂ and NO showed that reduction of TERT in the nucleus increased flow induced NO and decreased _mtH₂O₂ levels, while prevention of mitochondrial import of TERT augmented pathological effects. Further elevated _mtDNA damage was observed in tissue from subjects with CAD and initiation of _mtDNA repair mechanisms was sufficient to restore NO-mediated dilation in vessels from patients with CAD. The work presented is the first evidence that catalytically active mitochondrial TERT, independent of its nuclear functions, plays a critical physiological role in preserving NO-mediated vasodilation and the balance of mitochondrial to nuclear TERT is fundamentally altered in states of human disease that are driven by increased expression of dominant negative splice variants.

Author List

Ait-Aissa K, Norwood-Toro LE, Terwoord J, Young M, Paniagua LA, Hader SN, Hughes WE, Hockenberry JC, Beare JE, Linn J, Kohmoto T, Kim J, Betts DH, LeBlanc AJ, Gutterman DD, Beyer AM

Authors

Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Takushi Kohmoto MD, PhD Professor in the Surgery department at Medical College of Wisconsin

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

Coronary Artery Disease
Humans
Hydrogen Peroxide
Oxidation-Reduction
Telomerase
Vasodilation