AMP-Activated Protein Kinase and Sirtuin 1 Coregulation of Cortactin Contributes to Endothelial Function

• DOI: 10.1161/atvbaha.116.307871
• Publication Date: 2016-10-07T03:10:42Z
• Authors: Tzu-Pin Shentu; Ming He; Xiaoli Sun; Jianlin Zhang; Fan Zhang; Brendan Gongol; Traci L. Marin; Jiao Zhang; Liang Wen; Yinsheng Wang; Gregory G. Geary; Yi Zhu; David A. Johnson; John Y.-J. Shyy
• Keywords: Cortactin; Sirtuin 1

Cortactin translocates to the cell periphery in vascular endothelial cells (ECs) on cortical-actin assembly response pulsatile shear stress. Because cortactin has putative sites for AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) deacetylation, we examined hypothesis that AMPK SIRT1 coregulate dynamics stress.Analysis of ability phosphorylate recombinant oligopeptides whose sequences matched consensus pointed Thr-401 as site phosphorylation. Mass spectrometry confirmed Immunoblot analysis with siRNA human umbilical vein ECs EC-specific AMPKα2 knockout mice showed primes deacetylation analyses ECs, phospho-deficient T401A phospho-mimetic T401D mutant, or aceto-deficient (9K/R) aceto-mimetic (9K/Q) regulates nitric oxide synthase activity. Confocal imaging sucrose-density gradient revealed phosphorylated/deacetylated EC facilitating translocation from lipid nonlipid raft domains. Knockdown vitro genetic reduction expression vivo substantially decreased synthase-derived NO bioavailability. In vivo, atherosclerotic lesions increase ApoE-/-/cortactin+/- mice, when compared ApoE-/-/cortactin+/+ littermates.AMPK followed by modulates interaction Functionally, this AMPK/SIRT1 coregulated cortactin-F-actin is required subcellular translocation/activation atheroprotective.