# Pivotal Role of Mitochondrial Telomerase in Regulation of Vascular Tone and Redox Homeostasis

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $44,097

## Abstract

Telomerase, a ribo-nucleoprotein that counteracts telomere shortening, has recently been shown by our
investigative team to have a non-canonical role in attenuating formation of mitochondrial reactive oxygen species
(mtROS) in coronary arterioles from subjects with coronary artery disease (CAD). We demonstrated that
activation of TERT can reverse the mechanism of flow-induced endothelium-dependent dilation from H2O2 to
NO, restoring the phenotype to one observed in subjects without CAD. In this proposal, we aim to investigate
the mitochondria specific effects of telomerase activity and whether the dominant negative splice variant β-del
TERT is critical in this phenotypic change in dilator mechanism. Our central hypothesis is that mitochondrial DNA
damage is one of the underlying causes that leads to increase in ROS production. mtROS is known to promote
development of arteriolosclerosis and endothelial dysfunction, predisposing individuals to vascular
complications. NO has a well-known inhibitory effect on mtROS generation and has also been demonstrated to
increase telomerase. Whether nuclear or mitochondrial telomerase activity contributes to cardiovascular
protection is not defined. We developed novel inhibitors of nuclear (nucTERT) or mitochondrial (mitoTERT)
telomerase activity to differentiate the roles of nuclear and mitochondrial telomerase in mediating vascular
protective phenotypes. We will identify the role of mitochondrial telomerase in this change of mechanism from
health (NO mediation) to disease (H2O2 mediation) in mouse and human resistance vessels.
 We hypothesize that mitochondrial telomerase plays a protective role by preventing mtDNA damage in
normal conditions, while expression of β-del TERT in disease suppresses this protective effect and elevates
vascular cellular oxidative stress, and induces the conversion from NO to H2O2 as the mediator of FMD. This will
be tested by addressing two specific aims.
 Aim 1: We will determine whether mitochondrial localization of TERT is necessary and sufficient to
maintain NO rather than mtH2O2 as the mediator of flow-induced dilation in the human microcirculation.
 Aim2: we will investigate whether the mechanism by which CAD elicits a switch from NO to H2O2 as the
mediator of FMD and impairs mitochondrial function involves accumulation of β-del TERT. We will use existing
pharmacological and genetic tools that will lead to strategies for restoration of microvascular function in disease.
This novel hypothesis has important translational potential, identifying new therapeutic targets for moderating
the pathological changes associated with microvascular disease.

## Key facts

- **NIH application ID:** 10153003
- **Project number:** 3R01HL133029-04S1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Andreas M Beyer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $44,097
- **Award type:** 3
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153003

## Citation

> US National Institutes of Health, RePORTER application 10153003, Pivotal Role of Mitochondrial Telomerase in Regulation of Vascular Tone and Redox Homeostasis (3R01HL133029-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10153003. Licensed CC0.

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