geranylgeranyl-pyrophosphate and Hypercholesterolemia

High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Ab) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD.Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only amyloid precursor protein and Ab. The purpose of this review, therefore, was to examine the above-mentioned issues, discuss the pros and cons of the cholesterol-AD hypothesis, involvement of other lipids in the mevalonate pathway, and consider that AD may impact cholesterol homeostasis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Astrocytes; Cell Membrane; Cells, Cultured; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Humans; Hydroxycholesterols; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Mice; Models, Biological; Neurons; Polyisoprenyl Phosphates; Rabbits; Sesquiterpenes

In addition to their cholesterol-lowering effect, statins increase high-density lipoprotein cholesterol (HDL-C) levels. Endothelial lipase (EL) is a regulator of plasma HDL-C levels. In the present study, the effects of statins on EL expression were investigated.. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin suppressed basal and cytokine-treated EL expression in endothelial cells. Concomitant treatment with mevalonate or geranylgeranyl pyrophosphate completely reversed the inhibitory effect of pitavastatin, suggesting that geranylgeranylated proteins are involved in the inhibition of EL expression by statins. Inhibition of RhoA activity by overexpression of a dominant-negative mutant of RhoA or a Rho kinase inhibitor decreased EL levels. Pitavastatin reduced phospholipase activities of endothelial cells, and concomitant treatment with mevalonate reversed its inhibitory effect. Pitavastatin reduced RhoA activity and EL expression in mouse tissues. Furthermore, plasma EL concentrations in human subjects were measured by enzyme-linked immunosorbent assays. Plasma EL levels were negatively associated with plasma HDL levels in 237 patients with cardiovascular diseases, and pitavastatin treatment reduced plasma EL levels and increased HDL-C levels in 48 patients with hypercholesterolaemia.. These findings suggest that statins can reduce EL expression in vitro and in vivo via inhibition of RhoA activity. The inhibition of EL expression in the vessel wall may contribute to the anti-atherogenic effects of statins.

Topics: Adult; Aged; Aged, 80 and over; Animals; Cells, Cultured; Cholesterol, HDL; Dose-Response Relationship, Drug; Down-Regulation; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipase; Male; Mevalonic Acid; Mice; Mice, Inbred C57BL; Middle Aged; Polyisoprenyl Phosphates; Prospective Studies; Protein Kinase Inhibitors; Protein Prenylation; Quinolines; rho-Associated Kinases; rhoA GTP-Binding Protein; Time Factors; Transfection; Treatment Outcome

Hypercholesterolemia enhances platelet aggregability. Statins have beneficial effects on cardiovascular events. The purpose of this study is to investigate whether statins inhibit platelet aggregation and, if so, the mechanisms.. Twelve patients with hypercholesterolemia were prospectively randomized in a crossover design to receive either fluvastatin (20 mg/d) or colestimide (3000 mg/d) for 12 weeks. The subjects were switched to the opposite arm for additional 12 weeks. Before and after first and second treatments, experiments were performed. Eleven age-matched volunteers with normal lipid profiles served as controls. ADP-induced platelet aggregation, platelet-derive nitric oxide (PDNO) release, intraplatelet levels of GSH and GSSG, and intraplatelet nitrotyrosine production during platelet aggregation were measured. Fluvastatin and colestimide equally lowered total and low density lipoprotein cholesterol levels in hypercholesterolemia. Platelet aggregation was greater in hypercholesterolemia than in normocholesterolemia before treatment and was altered by fluvastatin. PDNO release, intraplatelet glutathione level, and GSH/GSSG ratio were lower in hypercholesterolemia than in normocholesterolemia before treatment and were increased by fluvastatin. Intraplatelet nitrotyrosine formation was greater in hypercholesterolemia than in normocholesterolemia, and decreased by fluvastatin. Colestimide did not have such effects. In vitro application of fluvastatin dose-dependently inhibited platelet aggregation. Furthermore, in vitro application of fluvastatin dose-dependently inhibited platelet nitrotyrosine expressions and the inhibitory effects by fluvastatin were reversed by preincubation with geranylgeranylpyrophosphate.. Fluvastatin altered platelet aggregability in hypercholesterolemic patients in a cholesterol-lowering independent manner, which was partly mediated by the improvement of intraplatelet redox imbalance.

Topics: Adult; Anion Exchange Resins; Blood Platelets; Cholesterol; Cross-Over Studies; Dose-Response Relationship, Drug; Epichlorohydrin; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glutathione; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Imidazoles; Indoles; Male; Middle Aged; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Platelet Aggregation; Polyisoprenyl Phosphates; Prospective Studies; Resins, Synthetic; Treatment Outcome; Triglycerides; Tyrosine

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) are widely used to reduce serum cholesterol in patients with hypercholesterolemia. Previous studies have shown that HRIs can induce apoptosis in colon cancer cells. In this study, we investigated the mechanisms underlying the apoptosis-inducing effect of HRIs in greater detail. The HRI lovastatin induced apoptosis in the human colon cancer cell line SW480 by blocking the cholesterol synthesis pathway. Immunoblot analysis of antiapoptotic molecules, including survivin, XIAP, cIAP-1, cIAP-2, Bcl-2, and Bcl-X(L), revealed that only survivin expression was decreased by lovastatin. Survivin down-regulation by RNA interference induced apoptosis, and survivin overexpression rendered the cells resistant to lovastatin-induced growth inhibition. These results indicate that survivin down-regulation contributes substantially to the proapoptotic properties of lovastatin. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate, two downstream intermediates in the cholesterol synthesis pathway, simultaneously reversed survivin down-regulation and the blocking of Ras isoprenylation by lovastatin. Ras isoprenylation is important for the activation of Ras-mediated signaling, including the activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. The PI3-kinase inhibitor down-regulated survivin in SW480 cells. In addition, lovastatin blocked Ras activation and Akt phosphorylation. We conclude that survivin down-regulation is crucial in lovastatin-induced apoptosis in cancer cells and that lovastatin decreases survivin expression by inhibiting Ras-mediated PI3-kinase activation via the blocking of Ras isoprenylation.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cholesterol; Colonic Neoplasms; Diterpenes; Down-Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; Hypercholesterolemia; Inhibitor of Apoptosis Proteins; Lovastatin; Microtubule-Associated Proteins; Neoplasm Proteins; Phosphorylation; Polyisoprenyl Phosphates; Protein Prenylation; RNA Interference; Sesquiterpenes; Signal Transduction; Survivin

The migration of circulating monocytes to the arterial wall during atherogenesis is largely modulated by activation of the CC chemokine receptor 2 (CCR2), a dominant monocyte chemotaxis receptor. The present study investigated whether 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition affects CCR2 gene expression and CCR2-dependent monocyte recruitment.. Competitive reverse transcription-polymerase chain reaction analysis and flow cytometry showed that simvastatin, an HMG-CoA reductase inhibitor, dose-dependently reduced monocyte CCR2 mRNA and protein expression. Treatment of 21 normocholesterolemic men with simvastatin (20 mg/d for 2 weeks) decreased CCR2 protein and mRNA expression in circulating monocytes. Promoter and electrophoretic mobility shift assays showed that simvastatin activated a peroxisome proliferator response element in THP-1 monocytes. Moreover, simvastatin-induced CCR2 downregulation was completely reversed by the synthetic peroxisome proliferator-activated receptor-gamma antagonist GW9662. Simvastatin-treated monocytes showed little chemotaxis movement in response to monocyte chemoattractant protein-1 (MCP-1), a specific CCR2 ligand. Treatment of C57/BL6 mice with simvastatin (0.2 microg/g body weight IP, daily for 1 week) inhibited transmigration of CD80+ monocytes to the MCP-1-injected intraperitoneal space. Moreover, few circulating inflammatory cells from simvastatin-treated Sprague-Dawley rats (0.2 microg/g body weight IP, daily for 2 weeks) were recruited to the aortic wall of hypercholesterolemic littermates.. The inhibition of CCR2/MCP-1-dependent monocyte recruitment by simvastatin may prevent excessive accumulation of monocytes in the arterial wall during atherogenesis.

Topics: Anilides; Animals; Aorta; Cells, Cultured; Chemokine CCL2; Chemotaxis, Leukocyte; Depression, Chemical; Diet, Atherogenic; Down-Regulation; Drug Evaluation, Preclinical; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Mevalonic Acid; Mice; Mice, Inbred C57BL; Monocytes; Polyisoprenyl Phosphates; PPAR gamma; Rats; Rats, Sprague-Dawley; Receptors, CCR2; Receptors, Chemokine; RNA, Messenger; Rosiglitazone; Sesquiterpenes; Simvastatin; Thiazolidinediones

Topics: Arteriosclerosis; Caveolin 1; Caveolins; Cell Division; Cholesterol; Cysteine Proteinase Inhibitors; Endothelium, Vascular; GTP-Binding Proteins; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Polyisoprenyl Phosphates; Sesquiterpenes; Signal Transduction; Superoxides