PLEIOTROPIC EFFECTS OF STATINS
James K. Liao, and Ulrich Laufs
Vascular Medicine Research, Brigham & Women's Hospital, Cambridge, Massachusetts 02139; email: jliao@rics.bwh.harvard.edu
Klinik Innere Medizin III, Universität des Saarlandes, 66421 Homburg, Germany; email: ulrich@laufs.com
▪ 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.
3 comments:
Nice theories, but look at the TIMI-22 study to see where "pleiotropic effects" get you.
Good Grief! Do you really think interfering with isoprenylation of proteins is a good thing? Think that biological process is just an unnecessary evolutionary hiccup? Do you really think Interfering with the function of Rho, Ras, RAb, is something desirable in basically well individuals?
http://molpharm.aspetjournals.org/cgi/content/abstract/58/6/1389
Molecular Pharamacology
Vol. 58, Issue 6, 1389-1397, December 2000
Inhibition of Protein Isoprenylation Impairs Rho-Regulated Early Cellular Response to Genotoxic Stress
Renate Gnad, Klaus Aktories, Bernd Kaina, and Gerhard Fritz
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Mainz, Germany (R.G., B.K., G.F.); and Institute of Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany (K.A.)
Activation of c-Jun N-terminal kinases (JNKs) and nuclear factor-B (NF-B) are early cellular responses to genotoxic stress involved in the regulation of gene expression. Pretreatment of cells with the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin blocked stimulation of JNK1 activity by UV irradiation and by treatment with the alkylating compound methyl methanesulfonate but did not affect activation of extracellular signal-regulated kinase 2 by UV light. Lovastatin also attenuated UV-induced degradation of the NF-B inhibitor IB. The effects of lovastatin on UV-triggered stimulation of JNK1 as well as on IB degradation were reverted by cotreatment with geranylgeranylpyrophosphate but not with farnesylpyrophosphate. Both a geranylgeranyltransferase type I inhibitor and a farnesyltransferase inhibitor blocked JNK1 stimulation by UV irradiation without impairing signaling to NF-B. This indicates that different types of isoprenylated proteins impair UV-induced signaling to JNK1 and NF-B, respectively. Since lovastatin caused a rapid decrease in the level of membrane-bound Rho GTPases, we hypothesize that Rho signaling is inhibited by lovastatin. In line with this hypothesis, Rho-inactivating toxin B from Clostridium difficile abolished both JNK1 activation and IB degradation evoked by UV irradiation. In summary, lovastatin-mediated inhibition of protein isoprenylation abrogates cellular stress responses involving JNK- and NF-B-regulated pathways, which seems to be caused by inactivation of Rho GTPases.
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Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics
Indeed, I m not in the business but let me tell you about the no-statin(no-.meaning nitric oxyde(donator)) wich NIcox is working on,
maybe it's the right way to stress the potential of the statins over the endothelial function?
PS/its always a pleasure to read your blog, even for a french! lol
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