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...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000382 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850219660881952768 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Santhosh Kumar Karthikeyan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4a5128cbc29d439d9d1dd596012a36e2 |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-4a5128cbc29d439d9d1dd596012a36e22025-08-20T02:07:19ZengElsevierRedox Biology2213-23172025-04-018110352510.1016/j.redox.2025.103525ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart diseaseSanthosh Kumar Karthikeyan0Palanisamy Nallasamy1Jarrell Matthew Cleveland2Ahila Arulmani3Ashvanthi Raveendran4Mariam Karimi5Mohammad Owais Ansari6Anil Kumar Challa7Moorthy P. Ponnusamy8Ivor J. Benjamin9Sooryanarayana Varambally10Namakkal S. Rajasekaran11Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USADepartment of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USADepartment of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USADepartment of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author. Division of Molecular & Cellular Pathology, Department of Pathology, UAB | The University of Alabama at Birmingham, Birmingham, AL, 35294-2180, USA.Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Medicine, University of Utah, School of Medicine, Salt Lake City, UT, USA; Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author. Cardiac Aging & Redox Signaling Laboratory, Center for Free Radical Biology, Division of Molecular & Cellular Pathology, Department of Pathology, UAB | The University of Alabama at Birmingham, BMR2 Room 533|901 19th Street South, Birmingham, AL, 35294-2180, USA.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.http://www.sciencedirect.com/science/article/pii/S2213231725000382Protein aggregationmiRNAReductive stressCardiomyopathyProteotoxomiRs |
| spellingShingle | 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 ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease Redox Biology Protein aggregation miRNA Reductive stress Cardiomyopathy ProteotoxomiRs |
| title | ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease |
| title_full | ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease |
| title_fullStr | ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease |
| title_full_unstemmed | ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease |
| title_short | ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease |
| title_sort | proteotoxomirs diagnostic and pathologic mirna signatures for reductive stress induced proteotoxic heart disease |
| topic | Protein aggregation miRNA Reductive stress Cardiomyopathy ProteotoxomiRs |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000382 |
| work_keys_str_mv | AT santhoshkumarkarthikeyan proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT palanisamynallasamy proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT jarrellmatthewcleveland proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT ahilaarulmani proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT ashvanthiraveendran proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT mariamkarimi proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT mohammadowaisansari proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT anilkumarchalla proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT moorthypponnusamy proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT ivorjbenjamin proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT sooryanarayanavarambally proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease AT namakkalsrajasekaran proteotoxomirsdiagnosticandpathologicmirnasignaturesforreductivestressinducedproteotoxicheartdisease |