title: Acetylation of cyclophilin A is required for its secretion and vascular cell activation.
abstract: OBJECTIVE
  Cyclophilin A (CyPA) is a pro-inflammatory mediator involved in oxidative stress-related cardiovascular diseases. It is secreted from vascular smooth muscle cell (VSMC) in response to reactive oxygen species (ROS) in a highly regulated manner. Extracellular CyPA activates VSMCs and endothelial cells (ECs) promoting inflammation, cell growth, and cell death. Recently, it was shown that acetylated CyPA (AcK-CyPA) affects its function. We investigated the role of acetylation of CyPA for its secretion and signalling in vascular cells.
  
  
  RESULTS
  We used angiotensin II (Ang II) to create sustained ROS and found significantly increased AcK-CyPA in VSMC. Site-directed mutagenesis showed that lysines K82 and K125 were the predominant CyPA residues acetylated in response to Ang II. Importantly, acetylation of K82 and K125 were required for Ang II-mediated CyPA secretion. ROS inhibitors, Tiron, and N-acetylcysteine inhibited Ang II-induced intracellular CyPA acetylation and also AcK-CyPA secretion. Using secreted CyPA from wild type and K82/125R mutants expressed in transduced VSMC or in vitro acetylated recombinant CyPA, we showed that extracellular AcK-CyPA significantly increased pERK1/2, matrix metalloproteinase-2 activation, and ROS production in VSMC compared with non-acetylated CyPA. Moreover, extracellular AcK-CyPA increased adhesion molecule expression (VCAM-1 and ICAM-1) in EC, which promoted monocyte adhesion.
  
  
  CONCLUSIONS
  ROS-dependent acetylation of CyPA is required for the generation of extracellular CyPA. Acetylated extracellular CyPA regulates VSMC and EC activation, suggesting that inhibition of acetylation of CyPA may prevent the pathogenesis of oxidative stress-related cardiovascular diseases.
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Box CVRI, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Nwe Nwe
authors.initials: NN
authors.lastname: Soe
authors.forename: Mark
authors.initials: M
authors.lastname: Sowden
authors.forename: Padmamalini
authors.initials: P
authors.lastname: Baskaran
authors.forename: Yeonghwan
authors.initials: Y
authors.lastname: Kim
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nigro
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Smolock
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D000107:Acetylation; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D021984:Cyclophilin A / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D021984:Cyclophilin A
keywords: Acetylation; Angiotensin II; Cyclophilin A; Endothelial Cell; HDAC; Oxidative stress; Vascular smooth muscle cell