Research Paper Volume 13, Issue 10 pp 13788—13806
Redd1 knockdown prevents doxorubicin-induced cardiac senescence
- 1 Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
- 2 Department of Geriatrics, Wuhan No.1 Hospital, Wuhan, Hubei 430022, China
- 3 Department of Radiology, Wuhan No.1 Hospital, Wuhan, Hubei 430022, China
- 4 Department of Otorhinolaryngology, First People’s Hospital of Yunnan Province, Kunming, Yunnan 650000, China
Received: October 14, 2020 Accepted: March 23, 2021 Published: May 6, 2021https://doi.org/10.18632/aging.202972
How to Cite
Copyright: © 2021 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.