Statins as cellular antithrombotics

In clinical trials, statins (vastatins) reduce cardiovascular disease with cholesterol reduction, but this relationship is unclear. We reasoned that ( 1)thrombin (Ila) is an underlying mediator of cardiovascular events, (2) Il a mediates cellular events through its primary receptor [protease-activated receptor-1 (PAR-1)], and (3) statins inhibit an isoprenoid-dependent event between PAR-1 activation and tissue factor upregulation leading to Ila gen eration. In the isoprenoid pathways, statins inhibit mevalonic acid synthes is prior to divergence of the cholesterol and other pathway branches, where the latter produce cell-regulating substances (e.g., ras proteins). Throug h PAR-1 in platelets and other cells, Ila stimulates G-protein-coupled mech anisms including ras proteins. We hypothesize that statins exhibit antithro mbotic properties at the cellular level downregulating Ila generation and t hat statins may constitute a novel class of antithrombotics. Copyright (C) 1999 S. Karger AG, Basel.