Atorvastatin induces tissue transglutaminase in human endothelial cells q Oliver Soehnlein a , Saeed Eskafi a , Alexander Schmeisser b , Heike Kloos a , Werner G. Daniel a , Christoph D. Garlichs a, * a Medical Clinic II, Friedrich-Alexander-University of Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany b Heart Center Dresden, University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany Received 9 July 2004 Available online 3 August 2004 Abstract Tissue transglutaminase (tTgase) contributes to the organisation of the basement membrane and is therefore thought to be im- portant for the integrity and stability of the vessel wall. In the present study, we hypothesised that the HMG-CoA reductase inhib- itor atorvastatin may up-regulate the tTgase expression in endothelial cells and thereby exert beneficial effects on endothelial function. Treatment of human umbilical vein endothelial cells (HUVEC) with atorvastatin (1–10 lM) caused a clear increased ex- pression of tTgase in both permeabilised and non-permeabilised HUVEC. In contrast, stimulation of HUVEC with TNFa had no substantial effect on tTgase expression or localisation but inhibited the atorvastatin-induced up-regulation and externalisation of tTgase. Propidium iodide staining revealed that statin-induced apoptosis is not responsible for the enhanced expression. By inducing the expression of tTgase, statins may promote tTgase-mediated stabilisation of the basement membrane. This effect of atorvastatin may contribute to the beneficial role of statins on endothelial function. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Tissue transglutaminase; Endothelial cells; Extracellular matrix; Atherosclerosis; Coronary heart disease Endothelial cells, apart from forming the barrier be- tween the bloodstream and the vessel wall, have also influ- ence on vessel structure, permeability, vessel tonus, platelet function, haemostasis, and inflammation [1,2]. The integrity of the endothelium is regulated on different levels such as intercellular contacts, adhesion molecules, basement membrane, and extracellular matrix. The extra- cellular matrix is an important determinant of plaque sta- bility in acute coronary syndromes. Mechanical forces and matrix metalloproteinase activity initiate plaque rup- ture, whereas tissue inhibitors of metalloproteinases have an important albeit indirect role in plaque stabilisation. Tissue transglutaminase (tTgase), a calcium-depen- dent enzyme that catalyses the formation of epsilon (c- glutamyl)lysine isopeptide bonds that are resistant to enzymatic, mechanical, and chemical degradation, is thought to stabilise the plaque directly. In particular, tTg- ase has been shown to cross-link components of the extra- cellular matrix, including fibronectin, vitronectin, laminin, and collagen [3–6]. Therefore, tTgase activity plays an important role in stabilisation of the basement membrane and adhesion of cells [7], which are important processes in wound healing, angiogenesis, and bone re- modelling [8–10]. The expression of tTgase was docu- mented in a variety of cell types, including endothelial cells, smooth muscle cells, and macrophages [11,12], which are major components of atherosclerotic lesions. Moreover, tTgase was found to be highly expressed along the luminal endothelium and in smooth muscle cells in coronary and carotid artery plaques [13]. At the sites of 0006-291X/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2004.07.087 q Abbreviations: tTgase, tissue transglutaminase; EC, endothelial cells; SMC, smooth muscle cells; HUVEC, human umbilical vein endothelial cells; TNFa, tumor necrosis factor a. * Corresponding author. Fax: +49 9131 482886. E-mail address: Christoph.Garlichs@med2.med.uni-erlangen.de (C.D. Garlichs). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 322 (2004) 105–109 BBRC