CD38 Deficiency Protects Heart from High Fat Diet-Induced Oxidative Stress Via Activating Sirt3/FOXO3 Pathway

Abstract

Background/Aims: Previous studies showed that CD38 deficiency protected heart from ischemia/reperfusion injury and high fat diet (HFD)-induced obesity in mice. However, the role of CD38 in HFD-induced heart injury remains unclear. In the present study, we have investigated the effects and mechanisms of CD38 deficiency on HFD-induced heart injury. Methods: The metabolites in heart from wild type (WT) and CD38 knockout (CD38^-/-) mice were examined using metabolomics analysis. Cell viability, lactate hydrogenase (LDH) release, super oxide dismutase (SOD) activity, reactive oxygen species (ROS) production, triglyceride concentration and gene expression were examined by biochemical analysis and QPCR. Results: Our results revealed that CD38 deficiency significantly elevated the intracellular glutathione (GSH) concentration and GSH/GSSG ratio, decreased the contents of free fatty acids and increased intracellular NAD⁺ level in heart from CD38^-/- mice fed with HFD. In addition, in vitro knockdown of CD38 significantly attenuated OA-induced cellular injury, ROS production and lipid synthesis. Furthermore, the expression of mitochondrial deacetylase Sirt3 as well as its target genes FOXO3 and SOD2 were markedly upregulated in the H9C2 cell lines after OA stimulation. In contrast, the expressions of NOX2 and NOX4 were significantly decreased in the cells after OA stimulation. Conclusion: Our results demonstrated that CD38 deficiency protected heart from HFD-induced oxidative stress via activating Sirt3/FOXO3-mediated anti-oxidative stress pathway.

CD38 Deficiency Alleviates D-Galactose-Induced Myocardial Cell Senescence Through NAD+/Sirt1 Signaling Pathway

“…NAD + concentrations were decreased in animals during aging and senescence (Verdin, 2015). Our previous study also demonstrated that CD38 played vital roles in adipogenesis and high fat induced oxidative stress (Wang et al, 2018a, b). But the role of CD38 in heart aging was unknown.…”

“…A number of evidences indicated that Sirtuin family had beneficial effects against age-associated damage and oxidative stress (Ho et al, 2009; Qiu et al, 2010; Someya et al, 2010; Tasselli et al, 2017). Our previous study showed that CD38 deficiency had protective roles in many cardiac diseases including ischemia/reperfusion injury, cardiac hypertrophy induced by Ang-II and lipid overload-induced heart injury (Guan et al, 2016; Guan et al, 2017; Wang et al, 2018a). However, whether CD38 affects heart aging and the mechanisms remains unknown.…”

NAD+ Metabolism as an Emerging Therapeutic Target for Cardiovascular Diseases Associated With Sudden Cardiac Death

“…In contrast, a CD38 inhibitor luteolinidin preserved NAD(P) + level, endothelial and myocardial function in an ex vivo heart I/R model (Boslett et al, 2017). The cardioprotective effect of CD38 deficiency have been shown to be SIRT1- (Guan et al, 2016) or SIRT3-dependent (Wang et al, 2018) in mouse models.…”

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

“…In the next section, we will briefly describe genes associated with NDgD as AD, PD, and HD that were discovered by a GWAS approach and meta-analysis ( Qi et al, 2012b ; Moss et al, 2017 ; Chang et al, 2018 ; Jansen et al, 2019 ) and that had previously shown strong association with monogenic or polygenic obesity ( Tong, 2011 ; Hatziri et al, 2018 ; Wang et al, 2018a , b ; Liu et al, 2019 ). Some of the genes mentioned below are APOE and TREM2 associated with AD; CD38 variants with AD and PD; and SYT4 with PD ( Chang et al, 2018 ; Jansen et al, 2019 ).…”