REVIEW: Statin Drugs and Dietary Isoprenoids Downregulate Protein Prenylation in Signal Transduction and Are Antithrombotic and Prothrombolytic Agents

J. W. Fenton, II^1,2*, W. P. Jeske³, J. L. Catalfamo⁴, D. V. Brezniak¹, D. G. Moon⁵, and G. X. Shen⁶

¹New York State Department of Health, Wadsworth Center, Albany, NY 12201-0509 USA; fax: 518-473-7082 or 2900; E-mail: brezniak@wadsworth.org

²Department of Physiology and Cell Biology and Department of Biochemistry and Molecular Biology, Albany Medical College, Albany, NY 12208 USA

³Cardiovascular Institute, Loyola University Medical Center, Maywood, IL 60153 USA

⁴College of Veterinary Medicine, Cornell University, Ithaca, NY 14852 USA

⁵Department of Biology, Albany College of Pharmacy, Albany, NY 12208 USA

⁶Departments of Internal Medicine and Physiology, University of Manitoba, Winnipeg, MB, R3E 3I7 Canada

^* To whom correspondence should be addressed.

Received May 22, 2001; Revision received June 20, 2001

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Statins and various isoprenoids of dietary origins inhibit L-mevalonic acid synthesis, which in turn downregulates cholesterol and various other dependent substances, including farnesyl- and geranylgeranyl-conjugated proteins involved in cell signaling processes. Such signaling processes are stimulated by protease-activated receptor-1 (PAR-1), which upon activation, causes the expression of various substances including tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1). Tissue factor promotes thrombin generation, where thrombin stimulates a variety of cellular processes, as well as activating PAR-1 to produce more thrombin. Statins downregulate TF mitigating thrombin generation and also downregulate PAI-1, which normally consumes tissue plasminogen activator (tPA). In the absence of PAI-1, tPA activates plasminogen to generate plasmin. Thus, statins behave as antithrombotic agents and prothrombolytic agents.

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KEY WORDS: statins, dietary isoprenoids, protein prenylation inhibition, protease-activated receptor mitigation, thrombin generation downregulation, plasmin generation upregulation

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