Mechanisms of Action

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HMG-CoA Reductase Inhibition and Protein Prenylation

The molecular mechanism(s) involved in many of the cholesterol-independent effects of statins have not been completely characterized. Most of these can be reversed by provision of supplemental mevalonate, indicating that inhibition of HMG-CoA reductase is responsible. The generation of mevalonate is the rate-limiting step in cholesterol synthesis (Figure 1). The next step is isopentenyl pyrophosphate (IPPP), which has an unknown function in mammalian cells but can modify tRNA. IPPP is the precursor of the isoprenoid compounds, farnesylpyrophosphate (FPP; C-15) and geranylgeranylpyrophosphate (GGPP; C-20). These lipid intermediates are required for post-translational modification of certain proteins by forming cysteine thioethers at their carboxy termini. Prenylated proteins include the Ras and Rho families of small GTP-binding signaling molecules. Prenylation allows localization to the cytoplasmic

Figure 1 Statin effects on the microvasculature. Effects of statins that target the endothelium and inflammation are critical to their vasculoprotective action. Although specific mechanisms remain to be fully elucidated, inhibition of geranylgeranylation is thought to play an important role. Rho is inhibited by statins, attenuating actin stress fiber formation. Although inhibition of Rac membrane translocation accounts for decreased ROS production, increased Rac activation by statins is associated with enhanced cortical actin and barrier protection (see text). (see color insert)

Endothelial Cell

I Rho hL

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Actin

I Rho hL

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I ROS Rac

Actin eNOS activity >, f Cell survival ^Adhesion molecules

Acetyl CoA HMG-CoA

Mevalonic acid Isoperitenyl-PP

Geranyl-PP Farnesyl-PP —

Geranrlgeranyl-PP

Squalene

Cholesterol

Anti-inflammatory/Immune Modulation

Inhibition of LFA-1 I Inducible MHC-II I Pro-inflammatory cytokines

Geranylgeranylated proteins surface of cell membranes where they can respond to upstream signals by converting from the inactive GDP-bound state to the active GTP-bound state, thereby transmitting a downstream signal (Figure 1). Intrinsic GTPase activity converts it back to the inactive GDP-bound state, releasing the bound downstream effector and allowing another cycle of signal transduction [2]. The Rho family (Rho, Rac, Cdc42, and others) is preferentially geranylger-anylated by the enzyme geranylygeranyl transferase (GGTase), whereas Ras is selectively farnesylated by farne-syl transferase (FTase). Many of the vascular actions of statins are antagonized by GGPP, but not FPP and mimicked by GGTase inhibitors, suggesting that inhibition of GGPP synthesis and Rho prenylation underlies these effects.

Functions of Rho-GTPases

The Rho family of small G-proteins are best known for their ability to mediate actin cytoskeletal reorganization. Rho activation promotes actin polymerization and myosin light chain phosphorylation, which lead to the formation of contractile actomyosin stress fibers. Rho-kinase (ROCK) is an important downstream effector of this process, which leads to intercellular gap formations between EC with disruption of barrier function and enhanced tone in VSMC. Rac activation produces lamellipodia and membrane ruffles and Cdc42 induces filopodia formation. Rho proteins are thus critical for many actin cytoskeleton-dependent processes, such as cell migration, adhesion, phagocytosis, and cytokinesis. Rho proteins can regulate gene expression via activa tion of c-jun N-terminal kinase (JNK), p38 mitogen—activated kinase and the transcription factors, serum response factor (SRF), and nuclear factor kB (NFkB). The Rho-GTPases are also required for G1 cell cycle progression, either through direct effects on gene transcription or due to their effects on the cytoskeleton.

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