Deletion of < em > Ulk1 < /em > inhibits neointima formation by enhancing KAT2A/GCN5-mediated acetylation of TUBA/ α-tubulin < em > in vivo < /em >

Autophagy. 2021 May 14:1-18. doi: 10.1080/15548627.2021.1911018. Online ahead of print.ABSTRACTULK1 (unc-51 like autophagy activating kinase) has a central role in initiating macroautophagy/autophagy, a process that contributes to atherosclerosis and neointima hyperplasia, or excessive tissue growth that leads to vessel dysfunction. However, the role of ULK1 in neointima formation remains unclear. We aimed to determine how Ulk1 deletion affected neointima formation and to investigate the underlying mechanisms. We measured autophagy activity, vascular smooth muscle cell (VSMC) migration and neointima hyperplasia in cultured VSMCs and ligation-injured mouse carotid arteries from male wild-type (WT, C57BL/6 J) and VSMC-specific ulk1 knockout (ulk1 KO) mice. Carotid artery ligation in WT mice increased ULK1 protein expression, and concurrently increased autophagic flux and neointima formation. Treating human aortic smooth muscle cells (HASMCs) with PDGF (platelet derived growth factor) increased ULK1 expression, activated autophagy, and promoted cell migration. Further, smooth muscle cell-specific deletion of Ulk1 suppressed autophagy, inhibited VSMC migration, and impeded neointima hyperplasia. Mechanistically, Ulk1 deletion inhibited autophagic degradation of histone acetyltransferase protein KAT2A/GCN5 (K[lysine] acetyltransferase 2A), resulting in accumulation of KAT2A that directly acetylated TUBA/α-tubulin and subsequently increased protein levels of acetylated TUBA. The a...

Source: Autophagy - May 14, 2021 Category: Cytology Authors: Changhan Ouyang Jian Li Xiaoxu Zheng Jing Mu Gloria Torres Qilong Wang Ming-Hui Zou Zhonglin Xie Source Type: research