# Reductive Stress Induces Proteotoxic Cardiac Disease

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $582,126

## Abstract

Conventionally, oxidative stress is considered pathological to cardiac protein quality control (PQC), which
rationalizes the therapeutic potential of antioxidants. However, many clinical trials of antioxidant
supplementation failed to deliver a positive impact and, rather, demonstrated adverse effects in various organs,
including those in the cardiovascular system. Emerging evidence suggests that reductive stress (RS), also
known as antioxidative stress, may cause ER stress and accumulation of mis/unfolded proteins. To fully
comprehend the molecular interplay underlying RS-mediated proteotoxicity and the time frame for myocardium
experiencing a transition from adaptive to maladaptive remodeling, it is critical to identify the molecular
participants, their dynamic interplay, and resulting sequential events (e.g., autophagy) that regulate PQC.
 Recently, our exciting and novel clinical observations revealed a link of chronic RS (cRS) underlying
disease progression of human heart failure (HF). We screened a selected group of HF patients (n=50, without
other major comorbidities) for their peripheral blood redox state; among them, a subset (n=8) displayed the RS
condition. Our proposed study will entail a translational component utilizing proteomics approaches and
molecular biology to better understand the etiology of RS in mouse models and to identify its relevance in HF
patients. Our central hypothesis is that cRS will alter proteome properties (e.g., protein dynamics & post-
translational modifications, or PTMs) and damage autophagy signaling, leading to persistent proteotoxicity and
cardiac dysfunction, thereby driving maladaptive remodeling in animal models and in human heart diseases.
We propose three aims: Aim 1 will determine altered protein dynamics, redistributed PTMs, and perturbed
autophagy subproteome in RS conditions. We will define the “reductome signatures” in control and cRS
phenotypes. Aim 2 will examine the impact of cRS on progressive damage of autophagy that may lead to
insufficient cargo-clearance and proteotoxicity in the myocardium over time. We will assess autophagosome
formation, autophagy flux, and protein folding capacity under cRS conditions and examine whether enhancing
autophagy delays and/or prevents proteotoxicity in mice. Aim 3 will examine the “redox phenotype” in the
peripheral blood of HF patients using HPLC based quantification of (a) GSH redox ratio, (b) lipid peroxidation,
and (c) total antioxidant capacity, as well as extract the molecular “reductome signatures” in HF patients with
RS using a computational platform to determine essential proteome features and regulatory pathways. This
aim will establish a translational value for the RS hypothesis in human HF.
 We have assembled a multidisciplinary team (scientists & physicians) with documented expertise in redox
biology, biochemistry, proteomics, and computational analyses. The genetic mouse models of RS, the
technology platforms, and the biochemical assays to ...

## Key facts

- **NIH application ID:** 9991889
- **Project number:** 5R01HL118067-08
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Rajasekaran Namakkal Soorappan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $582,126
- **Award type:** 5
- **Project period:** 2013-07-29 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991889

## Citation

> US National Institutes of Health, RePORTER application 9991889, Reductive Stress Induces Proteotoxic Cardiac Disease (5R01HL118067-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991889. Licensed CC0.

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