# Cysteine oxidation in the heart

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $606,770

## Abstract

Summary
Oxidative stress affects the function of signaling molecules through posttranslational modifications of cysteine
residues, which in turn regulate survival and death of cardiomyocytes (CMs) during myocardial stress. We
have shown that thioredoxin1 (Trx1), a 12 kD oxidoreductase, modulates the function of signaling molecules,
including HDAC4, AMPK, mTOR, and Atg7, in the heart by modulating their cysteine residues through either
thiol-disulfide exchange or transnitrosylation. Here we will investigate a novel role of cysteine oxidation in
mediating the degradation of sarcoplasmic reticulum (SR)/endoplasmic reticulum (ER) Ca2+ ATPase 2a
(SERCA2a) during heart failure and its regulation through non-canonical interaction between p22phox,
SERCA2a and Trx1. SERCA2a mediates Ca2+ reuptake into the SR/ER. Reduced contractility in the failing
heart caused by impaired Ca2+ cycling between the sarcoplasm and SR and SERCA2a downregulation are
important drivers of heart failure progression. Although rescue of SERCA2a using adeno-associated virus 9
(AAV9)-mediated delivery is effective in animals, it does not appear fully effective in heart failure patients.
Complex posttranslational modifications of SERCA2a, including oxidation, acetylation and SUMOylation, may
not allow effective restoration of SERCA2a function with the current strategy. Oxidation of SERCA2a induces
proteolysis through the ubiquitin proteasome system. We discovered that mice with cardiac-specific deletion of
p22phox are more susceptible to heart failure during pressure overload (PO) even though bulk production of
reactive oxygen species is attenuated. In depth studies of the underlying mechanism suggest that endogenous
p22phox binds to SERCA2a, protects SERCA2a from oxidation of cysteine residues, including Cys498, and
prevents Smurf1/Hrd1-mediated proteasome degradation of SERCA2a during oxidative stress in vitro. These
results suggest that p22phox plays a previously unrecognized role in the regulation of the function of SERCA2a
function through direct interaction. We will test the following hypotheses: 1. p22phox protects the heart against
heart failure in response to PO by stabilizing SERCA2a through direct interaction. 2. p22phox stabilizes
SERCA2a against oxidative stress by mediating SERCA2a-Trx1 interaction, inhibiting oxidation of
SERCA2a cysteines, including Cys498, and preventing SERCA2a-Smurf1/Hrd1 interaction. To test these
hypotheses, we will use newly generated genetically altered mouse models, including p22phox cardiac specific
knock-out and SERCA2a(C498S) knock-in mice. We will use proteomic approaches to evaluate
posttranslational modification of cysteine residues in SERCA2a and demonstrate thiol-disulfide exchange
between SERCA2a and Trx1. Our study will not only demonstrate a novel noncanonical function of p22phox but
also clarify the detailed mechanism through which oxidation of SERCA2a at previously unrecognized cysteine
residues leads to proteasomal degradation du...

## Key facts

- **NIH application ID:** 10802837
- **Project number:** 2R01HL091469-16
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Junichi Sadoshima
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,770
- **Award type:** 2
- **Project period:** 2008-01-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802837

## Citation

> US National Institutes of Health, RePORTER application 10802837, Cysteine oxidation in the heart (2R01HL091469-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10802837. Licensed CC0.

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