ABSTRACT
In recent years, the increase in available genetic information and a better understanding of the genetic bases of dyslipidemias has led to the identification of potential new avenues for therapies. Additionally, the development of new technologies has presented the key for developing novel therapeutic strategies targeting not only proteins (e.g., the monoclonal antibodies and vaccines) but also the transcripts (from antisense oligonucleotides (ASOs) to small interfering RNAs) or the genomic sequence (gene therapies). These pharmacological advances have led to successful therapeutic improvements, particularly in the cardiovascular arena because we are now able to treat rare, genetically driven, and previously untreatable conditions (e.g, familial hypertriglyceridemia or hyperchylomicronemia). In this review, the pre-clinical pharmacological development of the major biotechnological cholesterol lowering advances were discussed, describing facts, gaps, potential future steps forward, and therapeutic opportunities.
Subject(s)
Antibodies, Monoclonal , Anticholesteremic Agents , Antibodies, Monoclonal/adverse effects , Anticholesteremic Agents/adverse effects , Cholesterol, LDL , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides, Antisense/pharmacology , Cholesterol , Proprotein Convertase 9/geneticsABSTRACT
OBJECTIVE: Circulating monocytes adhere to the endothelium and migrate into the intima contributing to atherosclerotic plaque growth. Cigarette smoke is a risk factor for atherosclerosis, but it is not completely known how it affects monocyte behavior in atherogenesis. METHODS: We studied the effects of cigarette smoke condensate (CSC) on human monocytes (HM) chemotaxis and transmigration through an endothelial cell (EC) monolayer. RESULTS: Pre-treatment with CSC caused a decrease in HM chemotaxis and transmigration (-55% and -18% vs control, p < 0.05, respectively), paralleled by a reduced expression of Rac 1 GTPase. On the contrary, direct exposure of both HM and EC to CSC increased (+23% vs control, p < 0.05) HM transmigration, paralleled by a strong stimulation of VCAM1 and ICAM1 expression by ECs, and by a slight increase in monocyte integrin expression. An enhancement of monocyte transmigration was obtained after the exposure of both HM and EC to medium conditioned by HM previously incubated with CSC (+265% vs control, p < 0.001). CSC showed a stimulatory effect on the expression by HM of TLR4, MCP1, IL8, IL1beta, and TNFalfa, which was ablated by pre treatment with PDTC. Incubation with neutralizing antibodies against both MCP1 or IL8 completely abolished the CSC-conditioned medium induced HM transmigration. CONCLUSIONS: CSC induces HM to release chemotactic factor(s), which amplify the recruitment and transmigration of inflammatory cells through EC, but CSC may also reduce HM migratory capacity. Therefore, exposure to CSC affects monocyte behavior and interaction with the endothelium, thus potentially facilitating and/or further aggravating the atherogenic process.
Subject(s)
Chemotaxis, Leukocyte/drug effects , Endothelial Cells/drug effects , Monocytes/drug effects , Smoke/adverse effects , Smoking/adverse effects , Transendothelial and Transepithelial Migration/drug effects , Cell Line , Chemokine CCL2/metabolism , Coculture Techniques , Culture Media, Conditioned/metabolism , Dose-Response Relationship, Drug , Endothelial Cells/immunology , Endothelial Cells/metabolism , Humans , Intercellular Adhesion Molecule-1/metabolism , Interleukin-1beta/metabolism , Interleukin-8/metabolism , Monocytes/immunology , Monocytes/metabolism , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , rac1 GTP-Binding Protein/metabolismABSTRACT
Inflammation contributes importantly to all stages of atherosclerosis, including the onset of acute thrombotic complications. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. Moreover, statins have been shown to possess several pleiotropic properties independent of cholesterol lowering in experimental settings. Based on these premises, we investigated the anti-inflammatory and anti-atherothrombotic properties of rosuvastatin in vivo, testing its effect on cholesterol and monocyte accumulation, and on adhesion molecules and tissue factor (TF) expression. ApoE-deficient female mice were fed a cholesterol-rich diet containing rosuvastatin (0, 1, 2 or 10 mg kg(-1)d(-1)) for 12 weeks. Treatment with rosuvastatin did not significantly affect either body weight gain or plasma total cholesterol (C) and triglyceride levels. However, rosuvastatin treatment dose-dependently reduced ICAM-1 expression in the aortic valves (V) (up to 40% inhibition, p<0.05) and in the proximal segment of the ascending aorta (AA) (-50%, p<0.001). Similarly, rosuvastatin inhibited VCAM-1 expression in the V (-40%) and in the AA (-35%, p<0.05). Moreover, there was a reduced accumulation of macrophages in the V in a dose-dependent and statistically significant manner (-45%, p<0.01). These anti-inflammatory effects were reflected in a reduction of cholesterol deposition in the entire aorta, both in the free and in the esterified form. Finally, the expression of tissue factor, the most potent pro-thrombogenic agent, was consistently reduced in AA by rosuvastatin treatment (-71%, p<0.001). Altogether, these data demonstrate that rosuvastatin has anti-inflammatory and anti-atherothrombotic activities in apoE-deficient mice that could translate in a beneficial effect on atherogenesis.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Aorta/drug effects , Aortic Valve/drug effects , Apolipoproteins E/metabolism , Atherosclerosis/prevention & control , Cardiovascular Agents/pharmacology , Fluorobenzenes/pharmacology , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , Aorta/metabolism , Aorta/pathology , Aortic Valve/metabolism , Aortic Valve/pathology , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Atherosclerosis/chemically induced , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cardiovascular Agents/therapeutic use , Cholesterol/metabolism , Cholesterol, Dietary , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Fluorobenzenes/therapeutic use , Intercellular Adhesion Molecule-1/metabolism , Macrophages/drug effects , Macrophages/pathology , Mice , Mice, Knockout , Pyrimidines/therapeutic use , Rosuvastatin Calcium , Sulfonamides/therapeutic use , Thromboplastin/metabolism , Time Factors , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
Catechins are able to modulate the gelatinolytic activity of matrix metalloproteinase-9 (MMP-9) by reducing its release from macrophages. Gallocatechins decrease MMP-9 secretion by lowering MMP-9 promoter activity and mRNA levels. The effect appears to be dependent on some structural and stereochemical requirements. In this study, the relationship between chemical structure and activity was studied by testing the effect of analogues of (+/-)-gallocatechin-3-gallate (+/-)-GCG, selectively deprived of hydroxyl groups, on MMP-9 activity, transcription, and secretion. Our results indicate that (+/-)-GCG and (+/-)-catechin-3-gallate are characterized by a substitution pattern compatible with direct inhibition of MMP-9 activity. Conversely, when transcription was the target, (+/-)-trans-3-flavanol-3-benzoate, lacking all the hydroxyl groups, was the most effective both in lowering MMP-9 promoter activity and consequently protein secretion, and in inhibiting nuclear-factor-kappaB-driven transcription. Our results suggest that the structural requirements for enzyme inhibition are different from those necessary for targeting gene expression.
Subject(s)
Catechin/analogs & derivatives , Catechin/pharmacology , Matrix Metalloproteinase Inhibitors , Tissue Inhibitor of Metalloproteinases/pharmacology , Animals , Catechin/chemical synthesis , Catechin/chemistry , Cell Line , Cell Line, Tumor , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Humans , Macrophages/drug effects , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Molecular Structure , NF-kappa B/drug effects , NF-kappa B/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Several drugs or pharmacologically active molecules such as statins, calcium antagonists, and PPAR agonists have been shown to affect macrophage functions that contribute to atherosclerosis and modulate plaque stability. For example, the modulation of matrix metalloproteinase secretion and cholesterol metabolism in macrophages may help to prevent cardiovascular disease independently of the correction of risk factors.
Subject(s)
Cholesterol/metabolism , Macrophages/drug effects , Metalloproteases/metabolism , Animals , Calcium Channel Blockers/pharmacology , Cell Movement/drug effects , DNA-Binding Proteins/agonists , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Liver X Receptors , Macrophages/physiology , Orphan Nuclear Receptors , PPAR gamma/agonists , Receptors, Cytoplasmic and Nuclear/agonists , Selective Estrogen Receptor Modulators/pharmacology , Thromboplastin/geneticsABSTRACT
Excessive breakdown of extracellular matrix by metalloproteinases (MMPs) occurs in many pathological conditions, and thus inhibition of MMP activity might have therapeutic potential. The methanolic extract and the identified compounds from the bark of Tristaniopsis calobuxus Brongniart & Gris (Myrtaceae) were tested on the activity, production, and gene expression of MMP-9. The extract produced a concentration-dependent inhibition (50-95% at 10-50 microg/ml) of MMP-9 activity. The inhibitory activity was retained in the ethyl acetate-soluble fraction (50-95% inhibition at 10-50 microg/ml) which also reduced the release of MMP-9 by mouse peritoneal macrophages up to 80%. In the ethyl acetate-soluble fraction, two active fractions, 5A and 5B were identified. HPLC-MS and NMR analyses of these fractions indicated the presence of gallocatechin, ellagic acid, and its glycoside derivatives. Since the absolute configuration of gallocatechin was not determined, in the next experiments both (+)-gallocatechin (2R,3S) and (-)-gallocatechin (2S,3R) were tested, and (-)-epigallocatechin (2R,3R) was included for comparison. 5A and 5B inhibited MMP-9 secretion, an observation which correlated with the decrease of MMP-9 promoter activity and the downregulation of mRNA levels. All compounds decreased MMP-9 mRNA levels and secretion. Ellagic acid, (+)-gallocatechin and (-)-epigallocatechin, but not (-)gallocatechin inhibited promoter-driven transcription. Thus configuration at C2 (R) of the flavanol seem to be critical for the interaction with the promoter.
Subject(s)
Flavonoids , Gene Expression Regulation/drug effects , Matrix Metalloproteinase Inhibitors , Myrtaceae/chemistry , Phenols/isolation & purification , Phenols/pharmacology , Plant Bark/chemistry , Polymers/isolation & purification , Polymers/pharmacology , Animals , Genes, Reporter , Kinetics , Macrophages, Peritoneal/enzymology , Magnetic Resonance Spectroscopy , Matrix Metalloproteinase 9/genetics , Mice , Phenols/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Polymers/chemistry , Polyphenols , Promoter Regions, Genetic , RNA, Messenger/genetics , Recombinant Proteins/antagonists & inhibitors , Simian virus 40/genetics , TransfectionSubject(s)
Arteriosclerosis/pathology , Macrophages/physiology , ATP-Binding Cassette Transporters/physiology , Animals , Arteriosclerosis/complications , Arteriosclerosis/physiopathology , Chemotactic Factors/physiology , Coronary Artery Disease/complications , Coronary Artery Disease/pathology , Coronary Artery Disease/physiopathology , Disease Models, Animal , Extracellular Matrix/metabolism , Humans , Inflammation , Macrophages/enzymology , NF-kappa B/physiology , Receptors, Cytoplasmic and Nuclear/physiology , Thrombosis , Transcription Factors/physiologyABSTRACT
Activated macrophages within the arterial wall secrete matrix-degrading metalloproteinases (MMPs) that weaken the atherosclerotic plaque and contribute to its fissuration. Preclinical studies have shown that calcium antagonists may reduce atherogenesis in the arterial wall. In the present study we evaluated the effect of lacidipine on 92-kDa gelatinase B (MMP-9) expression in human macrophages in cultures. Cells were treated for 24 h with lacidipine and the conditioned media were analyzed. Lacidipine (1-20 microM) significantly reduced, in a dose-dependent manner, MMP-9 potential gelatinolytic capacity up to 50%. When MMP-9 expression was stimulated by treatment with phorbol esters or tumor necrosis factor-alpha, lacidipine was able to inhibit this enhanced gelatinolytic capacity up to 50 and 60%, respectively. Western blot analysis and enzyme-linked immunosorbent assay showed a reduction of MMP-9 protein actually released by cells. The addition of lacidipine in the incubation media determined no significant variation in Ca(2+) concentration. The drug did not affect MMP-9 mRNA levels, but it effectively reduced the amount of both active and total free MMP-9 secreted by human macrophages. Lacidipine reduced also the secretion of the tissue inhibitor of metalloproteinase-1 (TIMP-1); however we observed an overall reduction of the gelatinolytic activity of the cells. Finally, peritoneal macrophages, obtained from mice treated with lacidipine, showed a reduced secretion of MMP-9. Together, our data indicate that lacidipine may potentially exert an antiatherosclerotic activity by modulating the secretion of MMP-9 by macrophages. This, in addition to the previously demonstrated inhibition of cholesterol esterification, may contribute to increase plaque stability.
Subject(s)
Dihydropyridines/pharmacology , Macrophages/drug effects , Matrix Metalloproteinase 9/metabolism , Animals , Blotting, Western , Calcium Channel Blockers/pharmacology , Cells, Cultured , Electrophoresis, Polyacrylamide Gel , Humans , Macrophages/enzymology , Macrophages/metabolism , Matrix Metalloproteinase 9/drug effects , MiceABSTRACT
Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can induce the regression of vascular atherosclerosis and reduce cardiovascular-related morbidity and death in patients with and without coronary artery disease. It is usually assumed that these beneficial effects are due to the ability of statins to reduce cholesterol synthesis. However, because mevalonic acid is not only the precursor of cholesterol but also of many non-steroidal isoprenoid compounds, the inhibition of HMG-CoA reductase may lead to pleiotropic effects. As shown by the data reported in this review, some statins can interfere with major events involved in the formation of atherosclerotic lesions, regardless of their hypolipidemic properties. The relevance of these effects in humans remains to be established (particularly in view of the high statin doses required to produce a direct vascular action), thus their contribution to the reduction in cardiovascular events observed in clinical trials has become one of the major challenges for future studies aimed at clarifying the anti-atherosclerotic benefits of statins.
Subject(s)
Cardiovascular Diseases/prevention & control , Cholesterol/biosynthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipidemias/drug therapy , Hypolipidemic Agents/therapeutic use , Arteriosclerosis/drug therapy , Blood Coagulation/drug effects , Blood Platelets/drug effects , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/mortality , Dose-Response Relationship, Drug , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypolipidemic Agents/pharmacology , Inflammation/prevention & control , Lipoproteins, LDL/drug effects , Lipoproteins, LDL/metabolism , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Neovascularization, Physiologic/drug effects , Osteoporosis/prevention & control , Oxidation-Reduction/drug effects , Treatment OutcomeABSTRACT
Two key events in atherosclerotic plaque formation are the deposition of lipids in cells of the vascular wall, and migration and proliferation of arterial smooth muscle cells from the tunica intima toward the media. It has been shown that various calcium-channel antagonists may delay plaque formation in animal models. Among these, the new and highly lipophilic calcium antagonists, such as lacidipine and lercanidipine, display the most promising antiatherosclerotic activities. This paper will review and discuss these beneficial effects.
Subject(s)
Arteriosclerosis/prevention & control , Calcium Channel Blockers/pharmacology , Dihydropyridines/pharmacology , Cardiovascular System/cytology , Cardiovascular System/pathology , Cell Division , Cell Movement , Endothelium/drug effects , Endothelium/physiology , Humans , Lipid Metabolism , Macrophages/physiology , Muscle, Smooth/cytology , Myocardium/cytologyABSTRACT
OBJECTIVE: To investigate the direct anti-atherosclerotic properties of statins. RESEARCH DESIGN AND METHODS: Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been investigated. We studied the ability of statins to modulate modified LDL-induced cholesterol esterification, metalloproteinase secretion by macrophages, and arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the antiproliferative effect of sera from statin-treated patients has been confirmed in a cell culture system. RESULTS: Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC) migration and proliferation. Moreover, statins are able to reduce cholesterol accumulation in macrophages in vitro by blocking cholesterol esterification and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites (probably through prenylated protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of proliferating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their ability to reduce plasma cholesterol. Finally, ex vivo studies showed that sera from fluvastatin-treated patients interfere with SMC proliferation. CONCLUSIONS: These results suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effect in the arterial wall, beyond their effects on plasma lipids that could translate into a more significant prevention of cardiovascular disease. These findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients--a population with a higher absolute risk of recurrent cardiovascular events.
Subject(s)
Arteriosclerosis/drug therapy , Diabetes Mellitus/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Animals , Atorvastatin , Cell Division/drug effects , Cell Movement/drug effects , Cells, Cultured , Cholesterol/metabolism , Cholesterol Esters/metabolism , Diabetes Complications , Diabetic Angiopathies/prevention & control , Endocytosis/drug effects , Fatty Acids, Monounsaturated/pharmacology , Fluvastatin , Heptanoic Acids/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Indoles/pharmacology , Lipoproteins/metabolism , Lovastatin/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Macrophages, Peritoneal , Mice , Mice, Inbred BALB C , Muscle, Smooth/cytology , Pyridines/pharmacology , Pyrroles/pharmacology , Simvastatin/pharmacologyABSTRACT
The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events have generally been attributed to their hypocholesterolaemic properties. However, as mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions, effects other than cholesterol reduction may explain the pharmacological properties of statins. In the present review, we discuss the current knowledge on the nonlipid-related effects of statins, with a special emphasis on their potential benefits in different diseases, such as atherosclerosis and cancer. The mechanism(s) responsible for their favourable properties are also reviewed.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Animals , Arteriosclerosis/drug therapy , Blood Coagulation/drug effects , Blood Coagulation/physiology , Cholesterol/chemistry , Cholesterol, LDL/blood , Endothelium, Vascular/drug effects , Esterification , Fatty Acids, Monounsaturated/pharmacology , Fluvastatin , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Indoles/pharmacology , Pravastatin/pharmacology , Simvastatin/pharmacologyABSTRACT
Natural AECA constitute a pool of autoantibodies circulating in healthy subjects, which react with a restricted and conserved set of endothelial antigens and establish idiotypic interactions within the immunoglobulin networks. Normal IgG interacts with living endothelial cells and is internalized with a mechanism involving microtubules and resembling that of ligand-receptor internalization. IgG-endothelial cell interaction appears to be dependent on the variable region of antibodies and is followed by modifications of endothelial cell function. Natural AECA increase anti-inflammatory properties of endothelial cells through the selective inhibition of thromboxane A2, endothelin and metalloproteinase-9 secretion, and also through the inhibition of endothelial cell proinflammatory response to TNF-alpha. We have gathered evidence demonstrating that natural AECA constitute a strictly controlled autoantibody pool, interact with living endothelial cells and take part in the regulation of endothelial function, through direct anti-inflammatory effects.
Subject(s)
Autoantibodies/immunology , Endothelium, Vascular/immunology , Antibody Specificity , Autoantibodies/blood , Autoantigens , Cells, Cultured , Endothelin-1/metabolism , Endothelium, Vascular/metabolism , Humans , Immunity, Innate , Immunoglobulin Fragments/blood , Immunoglobulin Fragments/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Interleukin-6/metabolism , Matrix Metalloproteinase 9/metabolism , Thromboxane A2/metabolismABSTRACT
Apolipoprotein (apo) E isoforms are key determinants of susceptibility to Alzheimer's disease. The apoE4 isoform is the major known genetic risk factor for this disease and is also associated with poor outcome after acute head trauma or stroke. To test the hypothesis that apoE3, but not apoE4, protects against age-related and excitotoxin-induced neurodegeneration, we analyzed apoE knockout (Apoe-/-) mice expressing similar levels of human apoE3 or apoE4 in the brain under control of the neuron-specific enolase promoter. Neuronal apoE expression was widespread in the brains of these mice. Kainic acid-challenged wild-type or Apoe-/- mice had a significant loss of synaptophysin-positive presynaptic terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus. Expression of apoE3, but not of apoE4, protected against this excitotoxin-induced neuronal damage. ApoE3, but not apoE4, also protected against the age-dependent neurodegeneration seen in Apoe-/- mice. These differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of Alzheimer's disease and to the poor outcome after head trauma and stroke associated with apoE4 in humans.
Subject(s)
Apolipoproteins E/genetics , Brain Chemistry/genetics , Nerve Degeneration/genetics , Aging/metabolism , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/genetics , Animals , Apolipoprotein E3 , Apolipoprotein E4 , Apolipoproteins E/analysis , Apolipoproteins E/cerebrospinal fluid , Dendrites/chemistry , Dendrites/metabolism , Enzyme-Linked Immunosorbent Assay , Excitatory Amino Acid Agonists , Fluorescent Antibody Technique , Gene Expression Regulation, Developmental , Genotype , Humans , Kainic Acid , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Degeneration/chemically induced , Neurotoxins/metabolism , Presynaptic Terminals/chemistry , Presynaptic Terminals/metabolism , RNA, Messenger/analysis , Synaptophysin/analysisABSTRACT
Current treatment strategies and disease management programs for hyperlipidemia employ a range of lipid-lowering drugs. Results from early lipid-lowering trials using diet, fibrates, niacin and other classes of drug showed that lowering plasma cholesterol can significantly reduce the risk of developing ischemic cardiovascular events. The landmark statin trials have clearly demonstrated the benefits of lipid-lowering therapy in coronary heart disease (CHD) prevention and unlike early lipid-lowering studies, a reduction in mortality may become evident with statin therapy during the first year of treatment. The number of successful lipid-intervention trials continues to increase and evidence is accumulating that lipid modification can also reduce the risk of cardiovascular events among individuals with only modest degrees of blood-lipid abnormalities. With increasingly powerful drugs to modify blood lipids, the potential levels at which to initiate treatment and the appropriate target levels are rapidly changing and debate surrounds the question of where the line to initiate treatment should be drawn. The relative lack of major adverse events with statin therapy means that the level of CHD risk at which clinical benefit occurs cannot be determined by the degree of risk at which benefit exceeds adverse events. Therefore, patients with only moderately raised cholesterol levels can be treated because statin treatment is well tolerated. One of the most important aspects of the statin trials is the finding that clinical events, such as death and disability due to coronary artery disease, may be preventable or limited in a significant number of patients if they receive aggressive therapy. Current goals for cholesterol levels in patients with established CHD are rarely achieved with non-aggressive treatment; however, with aggressive lipid lowering statins can achieve these goals in a safe and effective manner.
Subject(s)
Cardiovascular Diseases/prevention & control , Hyperlipidemias/drug therapy , Hypolipidemic Agents/therapeutic use , Coronary Disease/blood , Coronary Disease/drug therapy , Humans , Lipids/bloodABSTRACT
We previously described a Sardinian family in which the probands had a severe form of hypercholesterolemia, suggestive of familial hypercholesterolemia (FH). However, low density lipoprotein (LDL) receptor activity in fibroblasts from these subjects and LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait. Sitosterolemia and pseudohomozygous hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoprotein (apo) B, sitosterolemia, and cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of LDL in 3 probands from these 2 families. 125I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19+/-0.01 versus 0.36+/-0.03 pools per day, respectively; P<0.001) and a significant increase in the production rate [20.7+/-4.4 versus 14. 0+/-2.4 mg. kg-1. d-1, respectively; P<0.01] of LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99mtechnetium-labeled LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appears to be caused by a selective reduction in hepatic LDL uptake. We propose that in this new lipid disorder, a recessive defect causes a selective impairment of LDL receptor function in the liver.
Subject(s)
Genes, Recessive , Hypercholesterolemia/genetics , Receptors, LDL/genetics , Adult , Apolipoprotein B-100 , Apolipoproteins B/metabolism , Cholesterol, LDL/metabolism , Family Health , Female , Humans , Hypercholesterolemia/metabolism , Italy , Kidney/chemistry , Kidney/metabolism , Kinetics , Liver/chemistry , Liver/metabolism , Male , Middle Aged , Myocardium/chemistry , Myocardium/metabolism , Pedigree , Receptors, LDL/metabolism , Spleen/chemistry , Spleen/metabolismABSTRACT
The beneficial effects of statins are assumed to result from their ability to reduce cholesterol biosynthesis. However, because mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may result in pleiotropic effects. It has been shown that several statins decrease smooth muscle cell migration and proliferation and that sera from fluvastatin-treated patients interfere with its proliferation. Cholesterol accumulation in macrophages can be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by human monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall environment as well. Although statins rarely have severe adverse effects, interactions with other drugs deserve attention. Simvastatin, lovastatin, cerivastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450-3A4, and are susceptible to drug interactions when co-administered with potential inhibitors of this enzyme. Indeed, pharmacokinetic interactions (e.g., increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of simvastatin or lovastatin and cyclosporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainly metabolized by cytochrome P450-2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, a 5- to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. In summary, statins may have direct effects on the arterial wall, which may contribute to their antiatherosclerotic actions. Furthermore, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.
Subject(s)
Anticholesteremic Agents/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Animals , Atorvastatin , Cell Division/drug effects , Cytochrome P-450 Enzyme System/physiology , Drug Interactions , Fatty Acids, Monounsaturated/pharmacology , Fluvastatin , Heptanoic Acids/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Indoles/pharmacology , Mevalonic Acid/metabolism , Pyridines/pharmacology , Pyrroles/pharmacology , Simvastatin/pharmacologyABSTRACT
-Macrophages secrete matrix metalloproteinases (MMPs) that may weaken the fibrous cap of atherosclerotic plaque, predisposing its fissuration. The 92-kDa gelatinase B (MMP-9) has been identified in abdominal aortic aneurysms and in atherosclerotic tissues. Fluvastatin, through the inhibition of the isoprenoid pathway, inhibits major processes of atherogenesis in experimental models (smooth muscle cell migration and proliferation and cholesterol accumulation in macrophages). We studied the effect of fluvastatin on the activity of MMP-9 in mouse and human macrophages in culture. Conditioned media of cells treated for 24 hours with fluvastatin were analyzed by gelatin zymography. In mouse macrophages, fluvastatin (5 to 100 micromol/L) significantly inhibited in a dose-dependent manner MMP-9 activity from 20% to 40% versus control. The drug, at a concentration as low as 5 micromol/L, inhibited MMP-9 activity ( approximately 30%) in human monocyte-derived macrophages as well. Phorbol esters (TPA, 50 ng/mL) stimulated MMP-9 activity by 50%, and fluvastatin inhibited this enhanced activity up to 50% in both mouse and human macrophages. The above results on the secretion of MMP-9 were confirmed by Western blotting and ELISA. The inhibitory effect of fluvastatin was overcome by the simultaneous addition of exogenous mevalonate (100 micromol/L), a precursor of isoprenoids. Fluvastatin's effect was fully reversible, and the drug did not cause any cellular toxicity. The statin did not block directly the in vitro activation of the secreted protease. Similar data were obtained with simvastatin. Altogether, our data indicate an inhibition of MMP-9 secretion by the drug. This effect is mediated by the inhibition of synthesis of mevalonate, a precursor of numerous derivatives essential for several cellular functions.
Subject(s)
Collagenases/metabolism , Fatty Acids, Monounsaturated/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Indoles/pharmacology , Macrophages, Peritoneal/drug effects , Animals , Cells, Cultured , Fluvastatin , Humans , Immunoblotting , Macrophages, Peritoneal/metabolism , Matrix Metalloproteinase 9 , Mice , Secretory Rate/drug effects , Simvastatin/pharmacologyABSTRACT
Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with APOE epsilon2 and epsilon3, APOE epsilon4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE epsilon4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE epsilon4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE epsilon4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.