Abstract
Our previous research showed that CD38 played vital roles in Ang-II induced hypertrophy and high fat diet induced heart injury. However, the role of CD38 in heart aging is still unknown. In the present study, we reported that CD38 knockdown significantly protected cardiomyocytes from D-galactose (D-gal)-induced cellular senescence. Cellular senescence was evaluated by β-galactosidase staining, the expressions of genes closely related to aging including p16 and p21, and the ROS production, MDA content and the expressions of oxidant stress related genes were examined by biochemical analysis, Western blot and QPCR. Our results showed that the expression of CD38 was increased in H9c2 cells after D-gal treatment and the expressions of NAMPT and Sirt1 were downregulated in heart tissue from old mice. CD38 knockdown significantly reduced the number of SA-β-gal-positive cells and the expressions of p16 and p21 in H9c2 cells with or without D-gal treatment. The acetylation level of total protein was decreased in CD38 knockdown group, but the expression of Sirt3 was increased in CD38 knockdown group treated with D-gal. In addition, knockdown of CD38 significantly attenuated D-gal induced ROS production, MDA content and NOX4 expression in the cells. Inhibition Sirt1 partially reversed the effects of CD38 knockdown on D-gal induced senescence and oxidative stress. Furthermore, NAD+ supplementation reduced D-gal induced cellular senescence, ROS production and MDA content. The expression of SOD2 was increased and the NOX4 expression was decreased in H9c2 cells after NAD+ supplementation. Taken together, our results demonstrated that CD38 knockdown alleviated D-gal induced cell senescence and oxidative stress via NAD+/Sirt1 signaling pathway.
Highlights
Senescence is a state of irreversible cellular arrest which is regulated by heredity and environmental factors
Our results showed that D-gal promoted cardiomyocytes senescence and increased reactive oxygen species (ROS) production, and the expression of CD38 was up-regulated in senescent cardiomyocytes, while the expressions of NAMPT and Sirt1 were down-regulated in old mice heart
These results suggested that 10 g/L D-gal could promote cellular senescence, and the CD38 expression was increased in D-gal treated cells
Summary
Senescence is a state of irreversible cellular arrest which is regulated by heredity and environmental factors. It has been founded that the content of NAD+ in heart and brain tissues was increased significantly in CD38 deficiency mice than wild-type mice (Aksoy et al, 2006). A study showed that CD38 gradually increased in tissues of liver, muscle and adipose during aging, and the involvement of CD38 in aging might be in part due to down-regulated Sirt activity (Camacho-Pereira et al, 2016). CD38 knockdown could attenuate myocardial cell aging and oxidative stress induced by D-gal, while Sirt specific inhibitor EX-527 reversed the effects of CD38 deficiency on senescence and oxidative stress. Our results revealed that the effects could be rescued by NAD+, suggesting that the NAD+/Sirt signaling may play important roles in myocardial cells aging induced by D-gal
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