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Updated: Nov 6, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Redd1 knockdown prevents doxorubicin-induced cardiac senescence
Pianpian Huang1,2, Lijuan Bai1, Lihua Liu1
1Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Abstract:
Regulated in development and DNA damage response-1 (Redd1) is a stress-response gene that is transcriptionally induced by diverse stressful stimuli to influence cellular growth and survival. Although evidence suggests that aging may drive Redd1 expression in skeletal muscles, the expression patterns and functions of Redd1 in senescent cardiomyocytes remain unspecified. To address this issue, in vitro and in vivo models of cardiomyocyte senescence were established by administration of doxorubicin (Dox). Redd1 overexpression and knockdown was achieved in cultured H9c2 cardiomyocytes and mouse tissues using, respectively, lentivirals and adeno-associated virus 9 (AAV9) vectors. In the hearts of both aged (24 months old) and Dox-treated mice, as well as in Dox-exposed H9c2 cardiomyocytes, high Redd1 expression accompanied the increase in both cellular senescence markers (p16INK4a and p21) and pro-inflammatory cytokine expression indicative of a stress-associated secretory phenotype (SASP). Notably, Redd1 overexpression accentuated, whereas Redd1 silencing markedly attenuated, Dox-induced cardiomyocyte senescence features both in vitro and in vivo. Notably, AAV9-shRNA-mediated Redd1 silencing significantly alleviated Dox-induced cardiac dysfunction. Moreover, through pharmacological inhibition, immunofluorescence, and western blotting, signaling pathway analyses indicated that Redd1 promotes cardiomyocyte senescence as a downstream effector of p38 MAPK to promote NF-kB signaling via p65 phosphorylation and nuclear translocation.
Insights
Regulated in development and DNA damage response-1 (Redd1) exacerbates cardiomyocyte senescence and cardiac dysfunction. Silencing Redd1 mitigates these effects, revealing its role in stress-induced heart aging.
Area of Science:
- Cardiovascular Biology
- Cellular Senescence
- Molecular Cardiology
Background:
- Regulated in development and DNA damage response-1 (Redd1) is a stress-response gene influencing cellular growth and survival.
- Aging and stress may increase Redd1 expression in skeletal muscles, but its role in senescent cardiomyocytes is unknown.
Purpose of the Study:
- To investigate the expression and function of Redd1 in senescent cardiomyocytes.
- To determine Redd1's role in doxorubicin (Dox)-induced cardiac senescence and dysfunction.
Main Methods:
- Established in vitro and in vivo models of cardiomyocyte senescence using doxorubicin (Dox).
- Utilized lentiviral and adeno-associated virus 9 (AAV9) vectors for Redd1 manipulation (overexpression and knockdown).
- Analyzed cellular senescence markers (p16INK4a, p21), stress-associated secretory phenotype (SASP), cardiac function, and signaling pathways (p38 MAPK, NF-kB).
Main Results:
- High Redd1 expression correlated with increased senescence markers and SASP in Dox-treated cardiomyocytes and aged/Dox-treated mouse hearts.
- Redd1 overexpression worsened Dox-induced senescence, while Redd1 silencing attenuated it both in vitro and in vivo.
- AAV9-mediated Redd1 silencing significantly improved Dox-induced cardiac dysfunction.
- Redd1 acts as a downstream effector of p38 MAPK, promoting NF-kB signaling via p65 phosphorylation and nuclear translocation to drive cardiomyocyte senescence.
Conclusions:
- Redd1 plays a critical role in promoting cardiomyocyte senescence and cardiac dysfunction.
- Redd1 functions as a key mediator in the p38 MAPK-NF-kB signaling pathway during stress-induced cardiac aging.
- Targeting Redd1 may offer a therapeutic strategy for mitigating age-related cardiac dysfunction and senescence.
