title: Statin drugs and dietary isoprenoids downregulate protein prenylation in signal transduction and are antithrombotic and prothrombolytic agents.
abstract: 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.
authors.affiliation: New York State Department of Health, Wadsworth Center, Albany, NY 12201-0509, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Fenton
authors.forename: W P
authors.initials: WP
authors.lastname: Jeske
authors.forename: J L
authors.initials: JL
authors.lastname: Catalfamo
authors.forename: D V
authors.initials: DV
authors.lastname: Brezniak
authors.forename: D G
authors.initials: DG
authors.lastname: Moon
authors.forename: G X
authors.initials: GX
authors.lastname: Shen
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015536:Down-Regulation; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D017368:Protein Prenylation; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000378:metabolism; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000924:Anticholesteremic Agents; D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D011106:Polyisoprenyl Phosphates; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D006160:Guanosine Triphosphate; D013925:Thromboplastin; D013917:Thrombin