Redd1 knockdown prevents doxorubicin-induced cardiac senescence

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 (p16(INK4a) 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.

Automated summary

Redd1 plays a crucial role in senescence of cardiomyocytes, with its high expression associated with increased cellular senescence markers and pro-inflammatory cytokine expression. It promotes cardiomyocyte senescence through the p38 MAPK/NF-kB signaling pathway.