Conclusion

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Statins have proved to be a crucial component of cardiovascular disease treatment. Much of their benefit may be unrelated to their cholesterol-lowering properties. A wide array of vasculoprotective actions has been described, the most potent targeting endothelial cells. The relatively strong safety profile of HMG Co-A reductase inhibitors in humans makes them an attractive pharmacologic class to study in other disease processes besides atherosclerosis. Moreover, delineation of the mechanisms involved in mediating their pleiotropic effects generates opportunities to develop novel compounds that can target a more specific pathway, e.g., LFA-1 inhibitors, Rho-kinase inhibitors, GGTase inhibitors, and potentially Akt activators.

Glossary

Actin stress fibers: Intracellular filaments in vascular endothelial cells formed by polymerization of actin and myosin leading to cell contracture and disruption of barrier function.

Angiogenesis: The process whereby endothelial cells of existing capillaries proliferate to form new vessels.

eNOS (endothelial nitric oxide synthase): The constitutively expressed isoform of the enzyme present in vascular endothelial cells and an important regulator of basal microvascular function.

Pleiotropic effects: A term used to describe the multiple cholesterol-independent actions of statins on vascular function and structure.

Prenylation or isoprenylation: Binding of lipid intermediates to protein signaling molecules.

Statins: A pharmacological class of drugs that competitively inhibit the rate rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase.

References

1. Mason, J. C. (2003). Statins and their role in vascular protection. Clin. Sci. (Lond.) 105(3), 251-266. A comprehensive review of the non-cholesterol-lowering effects of statins, including enhanced eNOS activity and the antithrombotic, antioxidant, and anti-inflammatory actions. The implications of the biphasic effects on angiogenesis are discussed. Cites 200 references.

2. Takai, Y., Sasaki, T., and Matozaki, T. (2001). Small GTP-binding proteins. Physiol. Rev. 81(1), 153-208.

3. Kureishi, Y., Luo, Z., Shiojima, I., Bialik, A., Fulton, D., Lefer, D. J., Sessa, W. C., and Walsh, K. (2000). The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogene-sis in normocholesterolemic animals. Nat. Med. 6(9), 1004-1010. This is the first study linking the enhanced eNOS activity to Akt stimulation and angiogenesis, both in vitro and in vivo in a mouse model of hind limb ischemia.

4. Wassmann, S., Laufs, U., Muller, K., Konkol, C., Ahlbory, K., Baumer, A. T., Linz, W., Bohm, M., and Nickenig, G. (2002). Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler. Thromb. Vasc. Biol. 22(2), 300-305.

5. Vecchione, C., and Brandes, R. P. (2002). Withdrawal of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors elicits oxidative stress and induces endothelial dysfunction in mice. Circ. Res. 91(2), 173-179. This study demonstrates attenuation of endothelium-dependent vasodilatation upon statin withdrawal in mice, due to increased vascular superoxide generation as a consequence of Rac-1 translocation, which was activated during statin treatment.

6. Weis, M., Heeschen, C., Glassford, A. J., and Cooke, J. P. (2002). Statins have biphasic effects on angiogenesis. Circulation 105(6), 739-745.

7. Dimmeler, S., Aicher, A., Vasa, M., Mildner-Rihm, C., Adler, K., Tiemann M., Rutten, H., Fichtlscherer, S., Martin, H., and Zeiher, A. M. (2001). HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J. Clin. Invest. 108(3), 391-397.

8. Skaletz-Rorowski, A., Lutchman, M., Kureishi, Y., Lefer, D. J., Faust, J. R., and Walsh, K. (2003). HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells. Cardiovasc. Res. 57(1), 253-264.

9. Weitz-Schmidt, G., Welzenbach, K., Brinkmann, V., Kamata, T., Kallen, J., Bruns, C., Cottens, S., Takada, Y., and Hommel, U. (2001). Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat. Med. 7(6), 687-692.

10. Stuve, O., Youssef, S., Steinman, L., Zamvil, S. S. (2003). Statins as potential therapeutic agents in neuroinflammatory disorders. Curr. Opin. Neurol. 16(3), 393-401.

Capsule Biography

Dr. Girgis is Associate Director of the Pulmonary Hypertension and Lung Transplant Programs at Johns Hopkins University. His research focuses on the effects of statins on vascular remodeling in pulmonary hypertension and is supported by the NIH and Pulmonary Hypertension Association.

Dr. Jacobson is a research fellow in the division of Pulmonary and Critical Care Medicine at Johns Hopkins. He is investigating the effects of statins on cytoskeletal rearrangement in endothelial cells.

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