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• W1969089946 abstract "Rauchhaus and colleagues1Rauchhaus M Coats AJS Anker SD The endotoxin-lipoprotein hypothesis.Lancet. 2000; 356: 930-933Summary Full Text Full Text PDF PubMed Scopus (453) Google Scholar contend that in patients with chronic heart failure reduction of LDL concentration could be harmful because this substance binds to and inactivates cytokine-releasing lipopoly-saccharide complexes. Central to their argument is the role of the cholesterol-lowering statin drugs, which also exhibit independent anti-inflammatory and anti-proliferative properties.Rauchhaus and colleagues propose that statin-like molecules that did not lower cholesterol but that retained these other beneficial properties would constitute good candidates to test the hypothesis. We suggest, however, that such non-cholesterol-lowering statins would not display the necessary ancillary properties.The primary action of statins at the molecular level is competitive inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase, which catalyses the conversion of HMG CoA to mevalonate, the rate-limiting step in the pathway leading to cholesterol biosynthesis (the mevalonate pathway). Assessment of this process shows that statin action additionally results in the inhibition of the synthesis of several intermediates.2Grünler J Ericsson J Dallner G Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins.Biochim Biophys Acta. 1994; 1212: 259-277Crossref PubMed Scopus (240) Google Scholar Depletion of these molecules probably leads to cholesterol-independent effects. Evidence shows that non-cholesterol-lowering effects of statins in a range of cell types and in animal models can be prevented (with a few exceptions) by coaddition of mevalonate,3Bellosta S Bernini F Ferri N et al.Direct vascular effects of HMG CoA reductase inhibitors.Atherosclerosis. 1998; 137: S101-S109Summary Full Text Full Text PDF PubMed Scopus (224) Google Scholar which suggests that they derive specifically from HMG CoA reductase inhibition. Thus, statins exert extra effects because the cholesterol-lowering action is indirect, rather than arising from interaction with other targets (the more common reason for side-effects). Statin-like molecules that do not lower cholesterol are, by definition, poor inhibitors of HMG CoA reductase and, therefore, we propose that such molecules would not produce the required non-cholesterol-lowering effects.A potentially fruitful approach might be to specifically target the actions of particular mevalonate-pathway inter-mediates. Candidates include the isoprenoids farnesol and geranyl-geraniol, which are synthesised in the mevalonate pathway in their pyrophosphate forms (FPP and GGPP, respectively).2Grünler J Ericsson J Dallner G Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins.Biochim Biophys Acta. 1994; 1212: 259-277Crossref PubMed Scopus (240) Google Scholar They covalently bind to small and heterotrimeric GTPase (G)-proteins in a post-translational modification process termed isoprenylation.2Grünler J Ericsson J Dallner G Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins.Biochim Biophys Acta. 1994; 1212: 259-277Crossref PubMed Scopus (240) Google Scholar This mechanism allows correct positioning and functioning of these signalling proteins. Isoprenylation is mediated by enzymes termed fernesyltransferases and geranyl-geranyltransferases (FTs and GGTs) that target different subsets of G-proteins. Specific natural and synthetic FT and GGT inhibitors (FTIs and GGTIs) inhibit isoprenylation in vitro and in animal models.4Hill BT Perrin D Kruczynski A Inhibition of RAS-targeted prenylation: protein farnesyl transferase inhibitors revisited.Crit Rev Oncol Hematol. 2000; 33: 7-23Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar FTIs are currently entering clinical trials as potential anticancer agents4Hill BT Perrin D Kruczynski A Inhibition of RAS-targeted prenylation: protein farnesyl transferase inhibitors revisited.Crit Rev Oncol Hematol. 2000; 33: 7-23Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar since the oncogenic G-protein RAS is modified by farnesol.5Kloog Y Cox AD Ras inhibitors: potential for cancer therapeutics.Mol Med Today. 2000; 6: 398-402Summary Full Text Full Text PDF PubMed Scopus (82) Google Scholar However, the wider potential for FTIs and GGTIs to act as a class of therapeutic agents exists in many other areas.In terms of testing the endotoxin-lipoprotein hypothesis, FTIs and GGTIs fulfil the requirement of acting on molecules of the mevalonate pathway, the likely statin ancillary property, but do not lower cholesterol (figure). Future development of inhibitors specific to individual G-proteins and other signalling molecules should provide even better candidates. Rauchhaus and colleagues1Rauchhaus M Coats AJS Anker SD The endotoxin-lipoprotein hypothesis.Lancet. 2000; 356: 930-933Summary Full Text Full Text PDF PubMed Scopus (453) Google Scholar contend that in patients with chronic heart failure reduction of LDL concentration could be harmful because this substance binds to and inactivates cytokine-releasing lipopoly-saccharide complexes. Central to their argument is the role of the cholesterol-lowering statin drugs, which also exhibit independent anti-inflammatory and anti-proliferative properties. Rauchhaus and colleagues propose that statin-like molecules that did not lower cholesterol but that retained these other beneficial properties would constitute good candidates to test the hypothesis. We suggest, however, that such non-cholesterol-lowering statins would not display the necessary ancillary properties. The primary action of statins at the molecular level is competitive inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase, which catalyses the conversion of HMG CoA to mevalonate, the rate-limiting step in the pathway leading to cholesterol biosynthesis (the mevalonate pathway). Assessment of this process shows that statin action additionally results in the inhibition of the synthesis of several intermediates.2Grünler J Ericsson J Dallner G Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins.Biochim Biophys Acta. 1994; 1212: 259-277Crossref PubMed Scopus (240) Google Scholar Depletion of these molecules probably leads to cholesterol-independent effects. Evidence shows that non-cholesterol-lowering effects of statins in a range of cell types and in animal models can be prevented (with a few exceptions) by coaddition of mevalonate,3Bellosta S Bernini F Ferri N et al.Direct vascular effects of HMG CoA reductase inhibitors.Atherosclerosis. 1998; 137: S101-S109Summary Full Text Full Text PDF PubMed Scopus (224) Google Scholar which suggests that they derive specifically from HMG CoA reductase inhibition. Thus, statins exert extra effects because the cholesterol-lowering action is indirect, rather than arising from interaction with other targets (the more common reason for side-effects). Statin-like molecules that do not lower cholesterol are, by definition, poor inhibitors of HMG CoA reductase and, therefore, we propose that such molecules would not produce the required non-cholesterol-lowering effects. A potentially fruitful approach might be to specifically target the actions of particular mevalonate-pathway inter-mediates. Candidates include the isoprenoids farnesol and geranyl-geraniol, which are synthesised in the mevalonate pathway in their pyrophosphate forms (FPP and GGPP, respectively).2Grünler J Ericsson J Dallner G Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins.Biochim Biophys Acta. 1994; 1212: 259-277Crossref PubMed Scopus (240) Google Scholar They covalently bind to small and heterotrimeric GTPase (G)-proteins in a post-translational modification process termed isoprenylation.2Grünler J Ericsson J Dallner G Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins.Biochim Biophys Acta. 1994; 1212: 259-277Crossref PubMed Scopus (240) Google Scholar This mechanism allows correct positioning and functioning of these signalling proteins. Isoprenylation is mediated by enzymes termed fernesyltransferases and geranyl-geranyltransferases (FTs and GGTs) that target different subsets of G-proteins. Specific natural and synthetic FT and GGT inhibitors (FTIs and GGTIs) inhibit isoprenylation in vitro and in animal models.4Hill BT Perrin D Kruczynski A Inhibition of RAS-targeted prenylation: protein farnesyl transferase inhibitors revisited.Crit Rev Oncol Hematol. 2000; 33: 7-23Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar FTIs are currently entering clinical trials as potential anticancer agents4Hill BT Perrin D Kruczynski A Inhibition of RAS-targeted prenylation: protein farnesyl transferase inhibitors revisited.Crit Rev Oncol Hematol. 2000; 33: 7-23Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar since the oncogenic G-protein RAS is modified by farnesol.5Kloog Y Cox AD Ras inhibitors: potential for cancer therapeutics.Mol Med Today. 2000; 6: 398-402Summary Full Text Full Text PDF PubMed Scopus (82) Google Scholar However, the wider potential for FTIs and GGTIs to act as a class of therapeutic agents exists in many other areas. In terms of testing the endotoxin-lipoprotein hypothesis, FTIs and GGTIs fulfil the requirement of acting on molecules of the mevalonate pathway, the likely statin ancillary property, but do not lower cholesterol (figure). Future development of inhibitors specific to individual G-proteins and other signalling molecules should provide even better candidates." @default.
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• W1969089946 title "Endotoxin-lipoprotein hypothesis" @default.
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