ORIGINAL ARTICLESStatins increase thrombomodulin expression and function in human endothelial cells by a nitric oxide-dependent mechanism and counteract tumor necrosis factor alpha-induced thrombomodulin downregulationShi, Jumeia; Wang, Junrua; Zheng, Huaiena; Ling, Wena; Joseph, Jacobb; Li, Dayuanb; Mehta, Jawahar Lb; Ponnappan, Ushac; Lin, Peid; Fink, Louis Md; Hauer-Jensen, Martina,dAuthor Information aDepartment of Surgery, bDepartment of Medicine, cDepartment of Microbiology-Immunology and dDepartment of Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA. Sponsorship: National Institutes of Health (Grant CA-83719). J.W. and J.S. contributed equally to this work. Correspondence and requests for reprints to Martin Hauer-Jensen, MD, PhD, Arkansas Cancer Research Center, 4301 West Markham, Slot 725, Little Rock, AR 72205, USA. Tel: +1 501 686 7912; fax: +1 501 421 0022; e-mail: email@example.com Received 17 March 2003 Revised 28 March 2003 Accepted 1 April 2003 Blood Coagulation & Fibrinolysis: September 2003 - Volume 14 - Issue 6 - p 575-585 Buy Abstract Expression of functionally active thrombomodulin (TM) on the luminal surface of endothelial cells is critical for vascular thromboresistance. TM maintains thrombohemorrhagic homeostasis by forming a complex with thrombin, which subsequently loses its procoagulant properties and instead activates protein C. Acquired deficiency of endothelial TM is of particular pathophysiological significance in sepsis and related disorders. We show here that two different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), atorvastatin and simvastatin, strongly increase the expression and functional activity of TM in human umbilical vein endothelial cells, human coronary artery endothelial cells, and EA.hy926 endothelial cells. The increase in endothelial TM conferred by statin was prevented by the addition of mevalonic acid, geranylgeranyl-pyrophosphate, and nitric oxide scavenger, and was mimicked by the addition of a specific inhibitor of geranylgeranyl transferase, as well as by nitric oxide donors. Moreover, statin counteracted tumor necrosis factor alpha-induced downregulation of endothelial cell TM. The increase in endothelial cell TM activity in response to statin constitutes a novel pleiotropic (non-lipid-related) effect of these commonly used compounds, and may be of clinical significance in disorders where deficient endothelial TM and protein C activation play a pathophysiological role. © 2003 Lippincott Williams & Wilkins, Inc.