Abstract
Background/Aims: Our and other studies showed that CD38 deficiency protected heart from ischemia/reperfusion injury and high fat diet (HFD)-induced obesity in mice, respectively. However, the roles of CD38 in lipid overload-induced heart injury were not evaluated. In the present study, we investigated the preventive effects and mechanisms of CD38 deficiency on mouse heart injury induced by HFD. Methods: The discrepant metabolites in heart from wild type (WT) and CD38 knockout (CD38 -/- ) mice fed with HFD were examined using metabolomics analysis. The cell viability, the lactate hydrogenase (LDH) release, super oxide dismutase (SOD) activity, reactive oxygen species (ROS) production, triglyceride concentration and the expressions of various corresponding genes were examined for evaluating the effects of CD38 on oleic acid (OA)-induced cell injury using CD38 knockdown H9C2 stable cell line. Results: Our results revealed that CD38 deficiency significantly elevated the intracellular glutathione (GSH) concentration and GSH/GSSG ratio, decreased the contents of various free fatty acids and increased intracellular NAD + level in heart of CD38 -/- mice fed with HFD. Knockdown of CD38 significantly attenuated OA-induced cell injury, ROS production and lipid synthesis, seen as enhancing cell viability, reducing LDH release, elevating SOD activity, and decreasing triglyceride content and expressions of FASN in the CD38 knockdown H9C2 stable cell line. In addition, we also observed that the mitochondrial deacetylase Sirt3 and its target genes FOXO3 and SOD2 were upregulated in the stable cell lines after OA stimulation. Furthermore, the expressions of NOX2 and NOX4 were attenuated, accompanied by decreasing Bax expression and increasing Bcl-2 expression in the cells after OA stimulation. Conclusions: Our results demonstrated that CD38 deficiency protected heart from HFD-induced oxidative stress via activating Sirt3/FOXO3-mediated anti-oxidative stress pathway.
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