Sirt1 overexpression inhibits fibrous scar formation and improves outcome after cerebral ischemic injury by deacetylation of 14-3-3ζ

Abstract

Abstract Fibrous scar is one of major factors for hindering synaptic regeneration after central neural system (CNS) injury. Silencing information regulator 2 related enzyme 1 (Sirt1) can regulate lung, liver, kidney and heart fibrosis. However, it is unclear how the fibrous scar forms and is regulated and it is unknown whether and how Sirt1 regulates formation of the fibrous scar after cerebral ischemic stroke. The present study tests whether and how Sirt1 affects formation of the fibrous scar following cerebral ischemic injury. Therefore, we examined the expression and localization and the effects of Sirt1 on the formation of the fibrotic scar after middle cerebral artery occlusion/reperfusion (MCAO/R) injury in vivoand transforming growth factor β1 (TGF-β1)-induced meningeal fibroblasts migration, proliferation, transdifferentiation and extracellular matrix (ECM) secretion. Finally, we explored the molecular mechanisms underlying the Sirt1-regulated fibrosis process in vitro. We found that MCAO/R injury induced fibrotic scar formation in the ischemic area accompanied with downregulation of Sirt1 expression. Overexpression of Sirt1 reduced the infarct volume in acute stage, alleviated loss of Nissl body and formation of fibrotic scar in middle and later periods, further promoted the synaptic plasticity and neurological function recovery. Similarly, Sirt1 expression is also downregulated during TGF-β1-induced fibrosis model. Sirt1 overexpression inhibited fibroblasts migration, proliferation, transdifferentiation into myofibroblasts and secretion of ECM by controlling deacetylation of lysine at K49 and K120 sites of 14-3-3ζ in vitro. Therefore, we believe Sirt1 can regulate fibrous scar formation and improve outcome after cerebral ischemic stroke through controlling deacetylation of 14-3-3ζ.