SIRT3 Deacetylates FOXO3 to Mediate Mitochondrial Biogenesis during Hypoxia

Endothelial cells (ECs) dysfunction plays a central role in the initiation and progression of cardiovascular diseases. Compared with other cells, ECs lining the vascular lumen not only are prone to, but also exhibit greater tolerance to the environmental perturbations such as hypoxic damage. Our current work indicates that mRNA and protein expression of Sirtuin 3 (SIRT3), a stress‐responsive deacetylase, are up‐regulated in ECs exposure to hypoxic (2% O2) condition. It has been reported that SIRT3 activates FOXO3 through deacetylation. The activity of FOXO3 is essential for the transcriptional expression of mitochondrial biogenesis‐related genes. We observed that FOXO3‐dependent induction of PGC‐1alpha, Trx II, Prx III and Prx V were up‐regulated by hypoxia. PGC‐1alpha is a master regulator of mitochondrial mass and activity, whereas Trx II, Prx III and Prx V detoxify ROS in mitochondria. Consequently, increased levels of mitochondrial mass and activity were detected under hypoxia. However, the hypoxia‐mediated inductions were repressed while knockdown of SIRT3 or ectopic expression of dominant negative SIRT3 gene in ECs. Thus, hypoxia induces SIRT3‐FOXO3 signaling to stimulate mitochondrial biogenesis. This mechanism may contribute the process of cellular adaptation to hypoxia in ECs.