ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease

ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease

Proteotoxic stress progressively leads to irreversible cardiac abnormalities. Using a mouse model of reductive stress-induced proteotoxic cardiomyopathy, we identified novel microRNA signatures, termed “ProteotoxomiRs,” which reflect stage-specific and transgene-specific responses to proteotoxic str...

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Bibliographic Details
Main Authors: Santhosh Kumar Karthikeyan, Palanisamy Nallasamy, Jarrell Matthew Cleveland, Ahila Arulmani, Ashvanthi Raveendran, Mariam Karimi, Mohammad Owais Ansari, Anil Kumar Challa, Moorthy P. Ponnusamy, Ivor J. Benjamin, Sooryanarayana Varambally, Namakkal S. Rajasekaran
Format: Article
Language:English
Published: Elsevier 2025-04-01
Series:Redox Biology
Subjects:
Protein aggregation
miRNA
Reductive stress
Cardiomyopathy
ProteotoxomiRs
Online Access:http://www.sciencedirect.com/science/article/pii/S2213231725000382
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Summary:Proteotoxic stress progressively leads to irreversible cardiac abnormalities. Using a mouse model of reductive stress-induced proteotoxic cardiomyopathy, we identified novel microRNA signatures, termed “ProteotoxomiRs,” which reflect stage-specific and transgene-specific responses to proteotoxic stress. Seven microRNAs were uniquely linked to the human mutant R120G-αB-Crystallin transgene, indicating their direct association with the pathogenic protein. Additionally, we uncovered two distinct microRNA profiles associated with the early (pre-onset) and late (cardiomyopathy/heart failure) stages of disease progression. Early-stage signatures primarily modulate signaling pathways essential for cardiac health, including mTOR and MAPK, while late-stage signatures reveal regulatory disruptions in calcium signaling and autophagy insufficiency, driving irreversible cardiac damage caused by reductive stress (RS) and proteotoxicity in transgenic mice. These findings reveal stage-specific miRNA biomarkers with potential diagnostic and prognostic value, offering new insights into the molecular underpinnings of proteotoxic cardiac disease. Moreover, our miRNA-mRNA interaction analysis uncovered potential targets unique to the transgene-specific, early, and late stages of the disease, including several promising druggable candidates, warranting further validation for translational applications.
ISSN:2213-2317

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