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Review
. 2008 Jan;14(1):37-44.
doi: 10.1016/j.molmed.2007.11.004.

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Chao-Yung Wang  1 , Ping-Yen Liu, James K Liao
Affiliations
Review

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Chao-Yung Wang et al. Trends Mol Med. 2008 Jan.

Abstract

Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance.

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Figures

Figure 1
Figure 1
Isoprenoids and statins. Diagram of the cholesterol biosynthesis pathway and the effects of HMG-CoA-reductase inhibition by statins. Inhibition of small GTPase isoprenylation by statins leads to modulation of various cellular functions. Abbreviations: eNOS: endothelial nitric oxide synthase; Map3K: mitogen-activated protein kinase kinase kinase; Pak: p21-activated kinase.
Figure 2
Figure 2
Regulation of the Rho GTPase cycle. Rho proteins cycle between a cytosolic, inactive GDP-bound state and an active, membrane, GTP-bound state. This cycle is controlled by guanine nucleotide-exchange factors (GEF), GTPase-activating proteins (GAP) and guanine nucleotide-dissociation inhibitors (GDI). After isoprenylation and translocation to the cell membrane, they interact with effectors and affect various cellular functions.
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