Sirtuin‐1 deacetylation of p53 plays a role in shear stress‐induced autophagy in endothelial cells

Abstract

Blood flow‐induced shear stress acted on endothelial cells (ECs) is essential for maintaining normal vascular function. Autophagy represents a homeostatic mechanism crucial for cell survival. In our current study, we demonstrate that shear stress to ECs increases autophagy and Sirtuin‐1 (SIRT1, a NAD+‐dependent deacetylase) deacetylation of tumor suppressor protein p53 may play a role. Human ECs subjected to shear stress (12 dynes/cm2) increased SIRT1 expression as well as NAD+/NADH ratio. ECs under shear stress stimulated autophagy as demonstrated by 1) an increase of LC3‐II/LC3‐I ratio and 2) a decrease of p62 level. Decrease or inhibition of p53 has been shown to induce autophagy and p53 degradation is facilitated with deacetylation by SIRT1. This study was aimed to understand whether p53 levels regulated by SIRT1 mediate shear stress‐induced autophagy. Shear stress to ECs induced SIRT1 expression whereas p53 acetylation (K382) and p53 levels were decreased. ECs treated with siRNA to knockdown SIRT1 or Sirt inhibitor (EX527) increased p53 acetylation and p53 level coupled with decreased autophagy. ECs treated with an activator (CTBP) of P300 (an acetyltransferase) to increase p53 acetylation resulted in an increase of p53 level and then lead to a decreased autophagy. ECs treated with SIRT1 activator (SRT1720) also decreased p53 acetylation and increased autophagy. Therefore, p53 level regulated by SIRT1 activity may at least partially play a role in shear stress‐induced autophagy in ECs. In conclusion, ECs under shear stress increase SIRT1 expression and the consequent decrease of p53 promotes autophagy and thus enhances endothelial homeostasis.