Pleiotropic effects of statins

Abstract

Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.

Figure 1

Structural basis of HMG-CoA reductase inhibition by statins. The active forms of statins resemble the cholesterol precursor, HMG-CoA (right panels). All statins share the HMG-like moiety and competitively inhibit the reductase by the similar mechanism but have distinct pharmacologic and pharmacodynamic properties related to their chemical structures (left panels, ball and stick graphs: black, carbon; red, oxygen; light blue, hydrogen; dark blue, nitrogen).

Figure 2

Biological actions of isoprenoids. Diagram of cholesterol biosynthesis pathway showing the effects of inhibition of HMG-CoA reductase by statins. Decrease in isoprenylation of signaling molecules, such as Ras, Rho, and Rac, leads to modulation of various signaling pathways. BMP-2: bone morphogenetic protein-2; eNOS: endothelial nitric oxide synthase; t-PA: tissue-type plasminogen activator; ET-1: endothelin-1; PAI-1: plasminogen activator inhibitor-1.

Figure 3

Regulation of Rho GTPase by isoprenylation. Rho proteins change between a cytosolic, inactive, GDP-bound state and an active, membrane, GTP-bound state. This cycle is controlled by several cofactors, including guanine nucleotide exchange factors (GEF), GTPase-activating proteins (GAP), and guanine nucleotide dissociation inhibitors (GDI). An important step in the activation of Rho GTPases is the posttranslational isoprenylation, which allows the translocation of Rho to the cell membrane and the subsequent activation.

Figure 4

Antioxidative mechanisms of statins. The core NAD(P)H oxidase comprises five components: p40^phox (PHOX for phagocyte oxidase), p47^phox, p67^phox, p22^phox, and gp91^phox. In the resting cell (left), three of these five components, p40^phox, p47^phox, and p67^phox,exist in the cytosol as a complex. The other two components, p22^phox and gp91^phox, are located in the membranes. When it is stimulated by angiotensin, the cytosolic component becomes heavily phosphorylated and the entire cytosolic complex migrates to the membrane. Activation requires the participation not only of the core subunits but also of two low-molecular-weight guanine nucleotide-binding proteins, Rac and Rap. During activation, Rac binds GTP and migrates to the membrane along with the core cytosolic complex. Treatment with statin down-regulates AT1-receptor expression and inhibits Rac1 GTPase, a necessary component of the NAD(P)H oxidase complex.

Figure 5

Relationship between LDL-C reduction and risk of cardiovascular events. (Left panel) Decrease in LDL-C (% reduction) is correlated with reduction in risk of nonfatal myocardial infarctions (MI) or coronary heart disease (CHD) among statin (WOSCOPS, CARE, and 4S) and nonstatin (LRC-CPPT and POSCH) trials. Note that the relationship (slope) holds between statin and nonstatin trials, suggesting that the beneficial effects of statins are likely due to only cholesterol lowering. (Right panel) Decrease in LDL-C (% reduction) is correlated with reduction in risk of nonfatal myocardial infarctions (MI) or coronary heart disease (CHD) among statin (WOSCOPS, CARE, and 4S) and nonstatin (LRC-CPPT and POSCH) trials after 4.5 years of treatment. Note that the nonstatin trials (LRC-CPPT and POSCH; dashed lines) show less cardiovascular benefits than statin trials (WOSCOPS, CARE, and 4S) and they no longer fall on the same slope (solid line).