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Investigate how chronic reductive stress driven by constitutive Nrf2 activation disrupts endoplasmic reticulum proteostasis and induces cardiomyopathy.

June 9, 2025Redox BiologyOpen Access

Reductive stress induces unresolved ER stress and proteotoxic cardiomyopathy

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Authors

SSSini SunnyUniversity of Alabama at Birmingham RRRajesh Kumar RadhakrishnanManipal Academy of Higher Education ADAsokan DevarajanUniversity of California, Los Angeles

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Implication

Preclinical mouse study demonstrates that chronic reductive stress triggers unresolved endoplasmic reticulum stress and proteotoxicity, leading to pathological cardiac remodeling and heart failure.

Key Points

Investigate how chronic reductive stress driven by constitutive Nrf2 activation disrupts endoplasmic reticulum proteostasis and induces cardiomyopathy.
Evaluated transgenic mice exhibiting constitutive cardiac Nrf2 activation under pro-reductive and reductive stress conditions, with high-expressing transgenic (TGH) models.
Conducted RNA-seq transcriptomic profiling, quantified redox balance (glutathione and ROS levels), and measured protein ubiquitination, aggregation, and proteasomal degradation capacity.
Assessed cardiac mechanics, myocardial dyssynchrony, and diastolic/systolic function using speckle-tracking echocardiography and the myocardial performance (TEI) index.
Chronic reductive stress altered ER gene expression in a dose-dependent manner, provoking redox imbalance with elevated glutathione, lowered ROS, and persistent unfolded protein response activation.
TGH hearts exhibited severe protein misfolding, ER dilation, increased ubiquitination, and proteotoxic protein aggregation alongside impaired proteasome activity and chaperone downregulation.
Speckle-tracking echocardiography revealed progressive strain abnormalities, dyssynchrony, elevated TEI index values indicating combined systolic/diastolic dysfunction, and Reticulon4/Nogo upregulation.

Cite This Study

Sunny et al. (2025) studied this question.

synapsesocial.com/papers/6a9fd419dfc81ffeb871e156 https://doi.org/10.1016/j.redox.2025.103713

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Implication

Preclinical mouse study demonstrates that chronic reductive stress triggers unresolved endoplasmic reticulum stress and proteotoxicity, leading to pathological cardiac remodeling and heart failure.

Reductive stress induces unresolved ER stress and proteotoxic cardiomyopathy

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Implication

Key Points

Cite This Study

Reductive stress induces unresolved ER stress and proteotoxic cardiomyopathy

Discussion

Member takes

Implication

Key Points

Cite This Study

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