CD38 promotes angiotensin II-induced cardiac hypertrophy.

Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 knockout mice were significantly resistant to oxidative stress such as H2 O2 -induced injury and hypoxia/reoxygenation-induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang-II)-induced cardiac hypertrophy. Following 14 days of Ang-II infusion with osmotic mini-pumps, a comparable hypertension was generated in both of CD38 knockout and wild-type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild-type mice compared with CD38 knockout mice. Consistently, RNAi-induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang-II-stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca2+ release induced by Ang-II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca2+ -NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.

Guan XH ，Hong X ，Zhao N ，Liu XH ，Xiao YF ，Chen TT ，Deng LB ，Wang XL ，Wang JB ，Ji GJ ，Fu M ，Deng KY ，Xin HB ... -  《-》

CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway.

Guan XH ，Liu XH ，Hong X ，Zhao N ，Xiao YF ，Wang LF ，Tang L ，Jiang K ，Qian YS ，Deng KY ，Ji G ，Fu M ，Xin HB ... -  《-》

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

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. 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. 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. Our results demonstrated that CD38 deficiency protected heart from HFD-induced oxidative stress via activating Sirt3/FOXO3-mediated anti-oxidative stress pathway.

Wang LF ，Huang CC ，Xiao YF ，Guan XH ，Wang XN ，Cao Q ，Liu Y ，Huang X ，Deng LB ，Deng KY ，Xin HB ... -  《-》

Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling.

Essick EE ，Ouchi N ，Wilson RM ，Ohashi K ，Ghobrial J ，Shibata R ，Pimentel DR ，Sam F ... -  《-》

A novel signaling pathway of ADP-ribosyl cyclase activation by angiotensin II in adult rat cardiomyocytes.

Gul R ，Kim SY ，Park KH ，Kim BJ ，Kim SJ ，Im MJ ，Kim UH ... -  《AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY》