# CARDIOPROTECTIVE EFFECTS OF THIOREDOXIN 1

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $558,624

## Abstract

Summary
Thioredoxin1 (Trx1) is a 12 kD oxidoreductase that reduces proteins with disulfide bonds through thiol-disulfide
exchange reactions. Trx1 attenuates mitochondrial dysfunction, pathological hypertrophy, and ischemic injury.
Trx1 directly interacts with signaling molecules and transcription factors, and regulates the function of its
targets through reduction of disulfide bonds at cysteine residues. We have identified class II HDACs, AMPK,
and mTOR as important targets of Trx1 in the heart. Trx1 also modulates protein S-nitrosylation through both
transnitrosylation and de-nitrosylation. Covalent modification by nitrosylation reversibly modifies the functions
of proteins. Although proteins can be nitrosylated directly by small molecules containing NO, such as S-
nitrosoglutathione, they can also receive NO from other proteins through transnitrosylation, which is highly
efficient and takes place in a regulated manner. Although Trx1 can act as either a de-nitrosylase or
transnitrosylase in non-cardiac cells, the role of endogenous Trx1 in controlling the level of protein S-
nitrosylation in the heart remains poorly understood. Furthermore, the molecular mechanism of
transnitrosylation is poorly understood. Our goal is to elucidate the role of Trx1 in mediating nitrosylation of
downstream targets in the heart. Our preliminary results suggest that Trx1 stimulates autophagy and protects
the heart in response to myocardial ischemia by mediating transnitrosylation of cardio-protective proteins,
including Atg7, an E1-like enzyme essential for autophagy. Furthermore, our results suggest that Cys73 in
Trx1 plays a critical role in the transnitrosylation of Atg7. We hypothesize that Atg7 is S-nitrosylated during
myocardial ischemia through Trx1 Cys73-mediated transnitrosylation. S-nitrosylation of Atg7 at
Cys294 and Cys402 plays an essential role in mediating autophagy, which in turn protects the heart
against myocardial ischemia. We will: 1. Demonstrate that endogenous Trx1 plays an important role in
mediating transnitrosylation of cardiac proteins involved in protection against myocardial ischemia. 2.
Demonstrate that Trx1 Cys73 plays an important role in mediating S-nitrosylation of Atg7. 3. Determine
whether prior intermolecular disulfide bond formation between Trx1 and Atg7 is required for transnitrosylation
of Atg7 by Trx1. 4. Demonstrate that Trx1 S-nitrosylates Atg7 at Cys294 and Cys402 and that S-nitrosylation of
Atg7 at Cys294 and/or Cys402 plays an important role in mediating autophagy during ischemia in vivo. We
have generated cardiac-specific Trx1 knockout mice, Trx1(C73S) knock-in (KI) mice, and Atg7 KI mice in
which Cys294 and/or Cys402 is mutated to serine(s). We will use a quantitative proteomic approach in
combination with the biotin switch method to identify Trx1 transnitrosylation targets. We will demonstrate a
novel role of Trx1 as a transnitrosylase during myocardial ischemia and Atg7 as a novel target of Trx1 whose
function is pro...

## Key facts

- **NIH application ID:** 10111546
- **Project number:** 5R01HL091469-14
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Junichi Sadoshima
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $558,624
- **Award type:** 5
- **Project period:** 2008-01-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111546

## Citation

> US National Institutes of Health, RePORTER application 10111546, CARDIOPROTECTIVE EFFECTS OF THIOREDOXIN 1 (5R01HL091469-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10111546. Licensed CC0.

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