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Isoprenoids as mediators of the biological effects of statins
James K. Liao
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
Address correspondence to: James K. Liao, Vascular Medicine Research, Brigham and Women’s Hospital, 65 Landsdowne Street, Room 275, Cambridge, Massachusetts 02139, USA. Phone: (617) 768-8424; Fax: (617) 768-8425; E-mail: jliao@rics.bwh.harvard.edu.
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Published August 1, 2002 - More info
J Clin Invest. 2002;110(3):285–288. https://doi.org/10.1172/JCI16421.
© 2002 The American Society for Clinical Investigation
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are potent inhibitors of cholesterol biosynthesis. Several large clinical trials have demonstrated the benefits of cholesterol lowering with these agents in the primary and secondary prevention of coronary heart disease. The overall clinical benefits observed with statin therapy, however, appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels.
Recent experimental and clinical evidence indicates that some of the cholesterol-independent, or so-called pleiotropic, effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response in the vascular wall. Many of these cholesterol-independent effects reflect statins’ ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. In particular, the inhibition of small GTP-binding proteins Rho, Ras, and Rac, whose proper membrane localization and function are dependent upon isoprenylation, may play an important role in mediating the biological effects of statins.
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Statins and isoprenylated proteins
By inhibiting L-mevalonic acid synthesis, statins also prevent the synthesis of other important isoprenoid intermediates of the cholesterol biosynthetic pathway, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) (15) (Figure 1). These intermediates serve as important lipid attachments for the posttranslational modification of a variety of cell-signaling proteins. Protein isoprenylation permits the covalent attachment, subcellular localization, and intracellular trafficking of membrane-associated proteins (16). Members of the Ras and Rho GTPase family are major substrates for posttranslational modification by isoprenylation and may be important targets for inhibition by statins. Indeed, statins induce changes in the actin cytoskeleton and assembly of focal adhesion complexes by inhibiting RhoA and Rac1 isoprenylation (Figure 2).
Figure 1Biological actions of isoprenoids and cholesterol. This diagram of the cholesterol biosynthesis pathway shows 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 2Actin cytoskeletal effects of statins. Phalloidin staining of human endothelial cells shows the effects of the statin simvastatin (10 μM) on actin stress fibers and focal adhesion complexes (green) with and without L-mevalonate (L-Mev, 200 μM).
Besides altering the actin cytoskeleton, inhibition of RhoA by statins increases endothelial nitric oxide synthase (eNOS) expression and decreases severity of cerebral ischemia in a mouse model of ischemic stroke (17, 18). Similarly, statins also increase the expression of tissue-type plasminogen activator (19) and inhibit the expression of plasminogen activator inhibitor-1 (19) and endothelin-1 by mechanisms involving inhibition of geranylgeranylation (20). Because Ras and Rho also regulate the cell cycle, they are, in addition, likely targets for the direct antiproliferative effects of statins. Indeed, statins inhibit vascular smooth muscle cell proliferation in transplant-associated arteriosclerosis (21) and may have clinical benefits in inhibiting certain breast cancers (22). Finally, inhibition of Rac1 geranylgeranylation and Rac1-mediated NAD(P)H oxidase activity by statins attenuates angiotensin II–induced reactive oxygen species production in vascular smooth muscle cells and cardiac myocytes (23, 24) (Figure 3). These cholesterol-independent antioxidant effects of statins lead to the inhibition of hypertrophic responses in these tissues.
Figure 3Antioxidant effects of statins. Intracellular oxidation (red) as determined by 2′,7′-dichlorofluoroscein staining of rat cardiomyocytes treated with angiotensin II (Ang II, 10 nM), with and without simvastatin (statin, 10 μM), L-mevalonate (L-Mev, 200 μM), GGPP (100 μM), or FPP (100 μM).
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