RESUMO
AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE*3Leiden.CETP mouse model. METHODS AND RESULTS: Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (-53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1ß (MIP-1ß/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (-64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control. CONCLUSIONS: AT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta.
Assuntos
Aterosclerose/prevenção & controle , Inibidores de PCSK9 , Vacinas de Subunidades Antigênicas/imunologia , Animais , Anticorpos/metabolismo , Doenças da Aorta/prevenção & controle , Apolipoproteína E3/deficiência , Biomarcadores/metabolismo , HDL-Colesterol/metabolismo , Doença das Coronárias/prevenção & controle , Modelos Animais de Doenças , Feminino , Hipercolesterolemia/imunologia , Hipercolesterolemia/prevenção & controle , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placa Aterosclerótica/prevenção & controle , Pró-Proteína Convertase 9/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vasculite/imunologia , Vasculite/prevenção & controleRESUMO
BACKGROUND: The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. The CETP inhibitor anacetrapib decreases (V)LDL-C by â¼15-40% and increases HDL-C by â¼40-140% in clinical trials. We evaluated the effects of a broad dose range of anacetrapib on atherosclerosis and HDL function, and examined possible additive/synergistic effects of anacetrapib on top of atorvastatin in APOE*3Leiden.CETP mice. METHODS AND RESULTS: Mice were fed a diet without or with ascending dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/day), atorvastatin (2.4 mg/kg/day) alone or in combination with anacetrapib (0.3 mg/kg/day) for 21 weeks. Anacetrapib dose-dependently reduced CETP activity (-59 to -100%, P < 0.001), thereby decreasing non-HDL-C (-24 to -45%, P < 0.001) and increasing HDL-C (+30 to +86%, P < 0.001). Anacetrapib dose-dependently reduced the atherosclerotic lesion area (-41 to -92%, P < 0.01) and severity, increased plaque stability index and added to the effects of atorvastatin by further decreasing lesion size (-95%, P < 0.001) and severity. Analysis of covariance showed that both anacetrapib (P < 0.05) and non-HDL-C (P < 0.001), but not HDL-C (P = 0.76), independently determined lesion size. CONCLUSION: Anacetrapib dose-dependently reduces atherosclerosis, and adds to the anti-atherogenic effects of atorvastatin, which is mainly ascribed to a reduction in non-HDL-C. In addition, anacetrapib improves lesion stability.
Assuntos
Anticolesterolemiantes/farmacologia , Aterosclerose/prevenção & controle , Ácidos Heptanoicos/farmacologia , Oxazolidinonas/farmacologia , Pirróis/farmacologia , Animais , Atorvastatina , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/efeitos dos fármacos , HDL-Colesterol/fisiologia , Progressão da Doença , Combinação de Medicamentos , Feminino , Ácidos Heptanoicos/administração & dosagem , Camundongos Transgênicos , Oxazolidinonas/administração & dosagem , Pirróis/administração & dosagem , Proteína Amiloide A Sérica/metabolismoRESUMO
Recently, we showed in APOE*3-Leiden cholesteryl ester transfer protein (E3L.CETP) mice that anacetrapib attenuated atherosclerosis development by reducing (V)LDL cholesterol [(V)LDL-C] rather than by raising HDL cholesterol. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP. E3L.CETP mice were fed a Western-type diet alone or supplemented with anacetrapib (30 mg/kg body weight per day). Microarray analyses of livers revealed downregulation of the cholesterol biosynthesis pathway (P < 0.001) and predicted downregulation of pathways controlled by sterol regulatory element-binding proteins 1 and 2 (z-scores -2.56 and -2.90, respectively; both P < 0.001). These data suggest increased supply of cholesterol to the liver. We found that hepatic proprotein convertase subtilisin/kexin type 9 (Pcsk9) expression was decreased (-28%, P < 0.01), accompanied by decreased plasma PCSK9 levels (-47%, P < 0.001) and increased hepatic LDL receptor (LDLr) content (+64%, P < 0.01). Consistent with this, anacetrapib increased the clearance and hepatic uptake (+25%, P < 0.001) of [(14)C]cholesteryl oleate-labeled VLDL-mimicking particles. In E3L mice that do not express CETP, anacetrapib still decreased (V)LDL-C and plasma PCSK9 levels, indicating that these effects were independent of CETP inhibition. We conclude that anacetrapib reduces (V)LDL-C by two mechanisms: 1) inhibition of CETP activity, resulting in remodeled VLDL particles that are more susceptible to hepatic uptake; and 2) a CETP-independent reduction of plasma PCSK9 levels that has the potential to increase LDLr-mediated hepatic remnant clearance.
Assuntos
VLDL-Colesterol/sangue , Dislipidemias/sangue , Hipolipemiantes/farmacologia , Oxazolidinonas/farmacologia , Pró-Proteína Convertases/sangue , Serina Endopeptidases/sangue , Animais , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Regulação para Baixo , Avaliação Pré-Clínica de Medicamentos , Dislipidemias/tratamento farmacológico , Dislipidemias/enzimologia , Feminino , Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Redes e Vias Metabólicas , Camundongos Transgênicos , Oxazolidinonas/uso terapêutico , Pró-Proteína Convertase 9RESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE*3Leiden.CETP mice. Mice received a Western-type diet and were treated with alirocumab (3 or 10 mg/kg, weekly subcutaneous dosing) alone and in combination with atorvastatin (3.6 mg/kg/d) for 18 weeks. Alirocumab alone dose-dependently decreased total cholesterol (-37%; -46%, P < 0.001) and TGs (-36%; -39%, P < 0.001) and further decreased cholesterol in combination with atorvastatin (-48%; -58%, P < 0.001). Alirocumab increased hepatic LDL receptor protein levels but did not affect hepatic cholesterol and TG content. Fecal output of bile acids and neutral sterols was not changed. Alirocumab dose-dependently decreased atherosclerotic lesion size (-71%; -88%, P < 0.001) and severity and enhanced these effects when added to atorvastatin (-89%; -98%, P < 0.001). Alirocumab reduced monocyte recruitment and improved the lesion composition by increasing the smooth muscle cell and collagen content and decreasing the macrophage and necrotic core content. Alirocumab dose-dependently decreases plasma lipids and, as a result, atherosclerosis development, and it enhances the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. In addition, alirocumab improves plaque morphology.
Assuntos
Anticorpos Monoclonais/farmacologia , Aterosclerose/tratamento farmacológico , Colesterol/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Macrófagos/metabolismo , Monócitos/metabolismo , Animais , Anticorpos Monoclonais Humanizados , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Colesterol/genética , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Macrófagos/patologia , Camundongos , Camundongos Transgênicos , Monócitos/patologiaRESUMO
LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. The therapeutic potential for PCSK9 inhibitors is highlighted by the fact that PCSK9 loss-of-function carriers exhibit 15-30% lower circulating LDL-C and a disproportionately lower risk (47-88%) of experiencing a cardiovascular event. Here, we utilized pcsk9(-/-) mice and an anti-PCSK9 antibody to study the role of the LDL receptor (LDLR) and ApoE in PCSK9-mediated regulation of plasma cholesterol and atherosclerotic lesion development. We found that circulating cholesterol and atherosclerotic lesions were minimally modified in pcsk9(-/-) mice on either an LDLR- or ApoE-deficient background. Acute administration of an anti-PCSK9 antibody did not reduce circulating cholesterol in an ApoE-deficient background, but did reduce circulating cholesterol (-45%) and TGs (-36%) in APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice, which contain mouse ApoE, human mutant APOE3*Leiden, and a functional LDLR. Chronic anti-PCSK9 antibody treatment in APOE*3Leiden.CETP mice resulted in a significant reduction in atherosclerotic lesion area (-91%) and reduced lesion complexity. Taken together, these results indicate that both LDLR and ApoE are required for PCSK9 inhibitor-mediated reductions in atherosclerosis, as both are needed to increase hepatic LDLR expression.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/metabolismo , Colesterol/sangue , Fígado/metabolismo , Pró-Proteína Convertases/metabolismo , Receptores de LDL/metabolismo , Serina Endopeptidases/metabolismo , Animais , Anticorpos/imunologia , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Feminino , Técnicas de Inativação de Genes , Humanos , Fígado/efeitos dos fármacos , Camundongos , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/deficiência , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/deficiência , Serina Endopeptidases/genética , Serina Endopeptidases/imunologiaRESUMO
Substantial efforts have been undertaken to identify and minimise factors responsible for the development of ventilator-induced lung injury. A novel approach to this problem addresses energy dissipated in lung tissue during the breathing cycle as one of the key problems. Flow-controlled ventilation is a new modality of mechanical ventilation based on a constant flow during both inspiration and expiration. This review aims to evaluate the current evidence available regarding flow-controlled ventilation. Lastly, three cases of flow-controlled ventilation application are presented: ventilation with a small lumen tube during tracheal resection, one-lung ventilation during thoracoscopic lobectomy, and ventilation of a critically ill patient with acute respiratory distress syndrome in an intensive care unit setting.
Assuntos
Síndrome do Desconforto Respiratório , Lesão Pulmonar Induzida por Ventilação Mecânica , Humanos , Pulmão , Respiração , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/terapia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controleRESUMO
The peroxisome proliferator-activated receptor alpha (PPARalpha) activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced very low density lipoprotein (VLDL)-TG clearance and decreased VLDL-TG production. However, because data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%) and TG (-60%) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles (-68%). This was associated with an increased post-heparin lipoprotein lipase (LPL) activity (+110%) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue, and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%) but not the VLDL-apolipoprotein B (apoB) production rate. Kinetic studies using [(3)H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma fatty acids and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver.
Assuntos
Fenofibrato/farmacologia , Lipoproteínas VLDL/metabolismo , Triglicerídeos/sangue , Animais , Apolipoproteínas B/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas HDL/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Triglicerídeos/metabolismoRESUMO
Cytochrome P450 3A (CYP3A) enzymes constitute an important detoxification system that contributes to primary metabolism of more than half of all prescribed medications. To investigate the physiological and pharmacological roles of CYP3A, we generated Cyp3a-knockout (Cyp3a-/-) mice lacking all functional Cyp3a genes. Cyp3a-/- mice were viable, fertile, and without marked physiological abnormalities. However, these mice exhibited severely impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel, displaying higher exposure levels in response to both oral and intravenous administration. These mice also demonstrated increased sensitivity to docetaxel toxicity, suggesting a primary role for Cyp3a in xenobiotic detoxification. To determine the relative importance of intestinal versus hepatic Cyp3a in first-pass metabolism, we generated transgenic Cyp3a-/- mice expressing human CYP3A4 in either the intestine or the liver. Expression of CYP3A4 in the intestine dramatically decreased absorption of docetaxel into the bloodstream, while hepatic expression aided systemic docetaxel clearance. These results suggest that CYP3A expression determines impairment of drug absorption and efficient systemic clearance in a tissue-specific manner. The genetic models used in this study provide powerful tools to further study CYP3A-mediated xenobiotic metabolism, as well as interactions between CYP3A and other detoxification systems.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Camundongos Knockout , Xenobióticos/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Docetaxel , Humanos , Camundongos , Camundongos Transgênicos , Microssomos/metabolismo , Fenótipo , Taxoides/administração & dosagem , Taxoides/farmacocinéticaRESUMO
BACKGROUND: Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiovascular death in the recent Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial. Therefore, we evaluated the antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP (E3L.CETP) mice. METHODS AND RESULTS: E3L.CETP mice were fed a cholesterol-rich diet without drugs or with torcetrapib (12 mg x kg(-1) x d(-1)), atorvastatin (2.8 mg x kg(-1) x d(-1)), or both for 14 weeks. Torcetrapib decreased CETP activity in both the absence and presence of atorvastatin (-74% and -73%, respectively; P<0.001). Torcetrapib decreased plasma cholesterol (-20%; P<0.01), albeit to a lesser extent than atorvastatin (-42%; P<0.001) or the combination of torcetrapib and atorvastatin (-40%; P<0.001). Torcetrapib increased high-density lipoprotein cholesterol in the absence (30%) and presence (34%) of atorvastatin. Torcetrapib and atorvastatin alone reduced atherosclerotic lesion size (-43% and -46%; P<0.05), but combination therapy did not reduce atherosclerosis compared with atorvastatin alone. Remarkably, compared with atorvastatin, torcetrapib enhanced monocyte recruitment and expression of monocyte chemoattractant protein-1 and resulted in lesions of a more inflammatory phenotype, as reflected by an increased macrophage content and reduced collagen content. CONCLUSIONS: CETP inhibition by torcetrapib per se reduces atherosclerotic lesion size but does not enhance the antiatherogenic potential of atorvastatin. However, compared with atorvastatin, torcetrapib introduces lesions of a less stable phenotype.
Assuntos
Aterosclerose/tratamento farmacológico , Ácidos Heptanoicos/farmacologia , Inflamação/induzido quimicamente , Pirróis/farmacologia , Quinolinas/farmacologia , Animais , Aterosclerose/patologia , Atorvastatina , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Sinergismo Farmacológico , Ácidos Heptanoicos/uso terapêutico , Camundongos , Camundongos Endogâmicos , Pirróis/uso terapêutico , Quinolinas/uso terapêuticoRESUMO
OBJECTIVE: Niacin potently decreases plasma triglycerides and LDL-cholesterol. In addition, niacin is the most potent HDL-cholesterol-increasing drug used in the clinic. In the present study, we aimed at elucidation of the mechanism underlying its HDL-raising effect. METHODS AND RESULTS: In APOE*3Leiden transgenic mice expressing the human CETP transgene, niacin dose-dependently decreased plasma triglycerides (up to -77%, P<0.001) and total cholesterol (up to -66%, P<0.001). Concomitantly, niacin dose-dependently increased HDL-cholesterol (up to +87%, P<0.001), plasma apoAI (up to +72%, P<0.001), as well as the HDL particle size. In contrast, in APOE*3Leiden mice, not expressing CETP, niacin also decreased total cholesterol and triglycerides but did not increase HDL-cholesterol. In fact, in APOE*3Leiden.CETP mice, niacin dose-dependently decreased the hepatic expression of CETP (up to -88%; P<0.01) as well as plasma CETP mass (up to -45%, P<0.001) and CETP activity (up to -52%, P<0.001). Additionally, niacin dose-dependently decreased the clearance of apoAI from plasma and reduced the uptake of apoAI by the kidneys (up to -90%, P<0.01). CONCLUSIONS: Niacin markedly increases HDL-cholesterol in APOE*3Leiden.CETP mice by reducing CETP activity, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool, and increases HDL-apoAI by decreasing the clearance of apoAI from plasma.
Assuntos
Apolipoproteína E3/metabolismo , Aterosclerose/tratamento farmacológico , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/metabolismo , Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , Niacina/farmacologia , Animais , Apolipoproteína A-I/metabolismo , Apolipoproteína E3/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Bile/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , Gorduras na Dieta/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fezes/química , Feminino , Humanos , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Fatores de Tempo , Triglicerídeos/sangue , Regulação para CimaRESUMO
AIM: This study was designed to investigate the effect of the angiotensin II receptor blocker olmesartan alone, or in combination with standard treatment with a statin, pravastatin, on atherosclerosis development in APOE*3Leiden transgenic mice. METHODS AND RESULTS: Four groups of 15 mice received an atherogenic diet alone (plasma cholesterol 17.4 +/- 2.7 mmol/l) or supplemented with either 0.008% (w/w) olmesartan (9.3 mg/kg per day) (plasma cholesterol 16.4 +/- 3.9 mmol/l), 0.03% (w/w) pravastatin (35 mg/kg per day) (plasma cholesterol 14.6 +/- 2.6 mmol/l), or the combination of both (plasma cholesterol 14.5 +/- 2.9 mmol/l) for 6 months. Treatment with olmesartan or pravastatin reduced the development of atherosclerosis as compared to the control group (-46 and -39%, respectively). Pravastatin also reduced the severity of the lesions. As compared to control the combination of both treatments almost fully prevented atherosclerosis (-91%, P < 0.001) and strongly reduced lesion number (-69%), lesion severity (-79%), number of macrophages (-89%) and T lymphocytes (-86%) per cross-section. Treatment with olmesartan alone and in combination with pravastatin inhibited the adhesion of monocytes to the vessel wall (-22%; P < 0.05 and -25%; P < 0.01, respectively), and reduced the relative quantity of macrophages in the lesions (-38%; P < 0.05 and -26%; NS, respectively) as compared to control. CONCLUSION: Olmesartan reduced atherosclerosis development mainly by decreasing monocyte adhesion and the relative amount of macrophages, whereas pravastatin inhibited the progression of atherosclerosis to more advanced lesions, reflecting different anti-atherosclerotic modes of action of the two drugs. Combination therapy with olmesartan and pravastatin additively reduced atherosclerosis development, resulting in less and less severe lesions.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Apolipoproteína E3/genética , Aterosclerose/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Imidazóis/administração & dosagem , Pravastatina/administração & dosagem , Tetrazóis/administração & dosagem , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Pressão Sanguínea/efeitos dos fármacos , Colágeno/metabolismo , Dieta Aterogênica , Sinergismo Farmacológico , Feminino , Humanos , Inflamação/prevenção & controle , Lipídeos/sangue , Macrófagos/patologia , Camundongos , Camundongos Transgênicos , Monócitos/patologia , Músculo Liso Vascular/patologia , Proteínas Recombinantes/genética , Proteína Amiloide A Sérica/metabolismo , Linfócitos T/patologiaRESUMO
Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This systematic review and meta-analysis investigated the effects of established and novel treatment strategies, specifically targeting HDL, on inhibition of atherosclerosis in cholesteryl ester transfer protein-expressing animals, and the prevention of clinical events in randomised controlled trials. Linear regression analyses using data from preclinical studies revealed associations for TC and non-HDL-C and lesion area (R(2)=0.258, P=0.045; R(2)=0.760, P<0.001), but not for HDL-C (R(2)=0.030, P=0.556). In clinical trials, non-fatal myocardial infarction risk was significantly less in the treatment group with pooled odd ratios of 0.87 [0.81; 0.94] for all trials and 0.85 [0.78; 0.93] after excluding some trials due to off-target adverse events, whereas all-cause mortality was not affected (OR 1.05 [0.99-1.10]). Meta-regression analyses revealed a trend towards an association between between-group differences in absolute change from baseline in LDL-C and non-fatal myocardial infarction (P=0.066), whereas no correlation was found for HDL-C (P=0.955). We conclude that the protective role of lowering LDL-C and non-HDL-C is well-established. The contribution of raising HDL-C on inhibition of atherosclerosis and the prevention of cardiovascular disease remains undefined and may be dependent on the mode of action of HDL-C-modification. Nonetheless, treatment strategies aimed at improving HDL function and raising apolipoprotein A-I may be worth exploring.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ensaios Clínicos Controlados Aleatórios como Assunto , Animais , HumanosRESUMO
BACKGROUND AND PURPOSE: Salsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested before, the potential of salsalate to protect against non-alcoholic steatohepatitis (NASH) remains unclear. The aim of the present study was therefore to ascertain the effects of salsalate on the development of NASH. EXPERIMENTAL APPROACH: Transgenic APOE*3Leiden.CETP mice were fed a high-fat and high-cholesterol diet with or without salsalate for 12 and 20 weeks. The effects on body weight, plasma biochemical variables, liver histology and hepatic gene expression were assessed. KEY RESULTS: Salsalate prevented weight gain, improved dyslipidemia and insulin resistance and ameliorated diet-induced NASH, as shown by decreased hepatic microvesicular and macrovesicular steatosis, reduced hepatic inflammation and reduced development of fibrosis. Salsalate affected lipid metabolism by increasing ß-oxidation and decreasing lipogenesis, as shown by the activation of PPAR-α, PPAR-γ co-activator 1ß, RXR-α and inhibition of genes controlled by the transcription factor MLXIPL/ChREBP. Inflammation was reduced by down-regulation of the NF-κB pathway, and fibrosis development was prevented by down-regulation of TGF-ß signalling. CONCLUSIONS AND IMPLICATIONS: Salsalate exerted a preventive effect on the development of NASH and progression to fibrosis. These data suggest a clinical application of salsalate in preventing NASH.
Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Salicilatos/uso terapêutico , Alanina Transaminase/sangue , Animais , Apolipoproteínas E/genética , Aspartato Aminotransferases/sangue , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/genética , Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Salicilatos/farmacologiaRESUMO
Hypertension and hyperlipidaemia are major risk factors for the development of atherosclerosis. Calcium channel blockers (CCBs) have been used for decades and have established antihypertensive effects. Statins have been extensively used because of their potent lipid lowering properties. Amongst other factors, inflammation and oxidation are involved in enhanced progression of atherosclerosis and new lesion development. Therefore, research has been initiated focusing on the antioxidant and anti-inflammatory properties of CCBs and statins, beyond their primary effect, in order to evaluate the possible additive effects of combined treatment of CCBs with statins as antiatherosclerotic therapy. Clinical studies (e.g., the International Nifedipine Trial on Antiatherosclerotic Therapy [INTACT]) have demonstrated that the antiatherosclerotic action of CCBs is limited to the attenuation of the first stage of atherosclerogenesis (fatty streak formation or new lesion growth). The lesions that pre-existed at the start of CCB therapy did not demonstrate progression or regression on angiography. However, because the mechanisms of action of lipid-lowering drugs and CCBs, and their role in preventing the progression of atherosclerosis differ, it is conceivable to conclude that these two classes may have an additive or synergic effect, not only on new lesion formation but also on inhibiting the progression of established coronary atherosclerosis. Indeed, this combined effect of lipid-lowering therapy and CCBs on human coronary atherosclerosis has been reported in the Regression Growth Evaluation Statin Study (REGRESS) trial. This beneficial effect of combining CCBs with statins has now been replicated in transgenic atherosclerotic mice, where the combination of amlodipine and atorvastatin produced an additional 60% reduction of atherosclerosis compared with that observed with the statin alone. Serum markers of atherosclerosis and vascular integrity also improved most in the combination group. Synergistic effects of the combination of atorvastatin and amlodipine on acute nitric oxide release/endothelial function, and additive effects of the combination of amlodipine and atorvastatin in the improvement of arterial compliance in hypertensive hyperlipidaemic patients has been demonstrated. Collectively, these studies support the clinical antiatherosclerotic advantages of combination of CCBs and statins and in particular, of atorvastatin with amlodipine beyond their established antihyperlipidaemic and antihypertensive modes of action.
Assuntos
Anlodipino/uso terapêutico , Arteriosclerose/tratamento farmacológico , Terapia Combinada , Ácidos Heptanoicos/uso terapêutico , Pirróis/uso terapêutico , Anlodipino/farmacologia , Animais , Arteriosclerose/fisiopatologia , Atorvastatina , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Ácidos Heptanoicos/farmacologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Pirróis/farmacologiaRESUMO
UNLABELLED: The experimental autoimmune encephalomyelitis model is a model of multiple sclerosis that closely mimics the disease characteristics in humans. The main hallmarks of multiple sclerosis are neuroinflammation (microglia activation, monocyte invasion, and T-cell infiltration) and demyelination. PET imaging may be a useful noninvasive technique for monitoring disease progression and drug treatment efficacy in vivo. METHODS: Experimental autoimmune encephalomyelitis was induced by myelin-oligodendrocyte glycoprotein immunization in female Dark Agouti rats. Experimental autoimmune encephalomyelitis rats were imaged at baseline and at days 6, 11, 15, and 19 after immunization to monitor monocyte and microglia activation ((11)C-PK11195) and demyelination ((11)C-MeDAS) during normal disease progression and during treatment with dexamethasone. RESULTS: (11)C-PK11195 PET detected activation of microglia and monocytes in the brain stem and spinal cord during disease progression. The uptake of (11)C-PK11195 was elevated in dexamethasone-treated animals that had shown mild clinical symptoms that had resolved at the time of imaging. Demyelination was not detected by (11)C-MeDAS PET, probably because of the small size of the lesions (average, 0.13 mm). CONCLUSION: PET imaging of neuroinflammation can be used to monitor disease progression and the consequences of treatment in the experimental autoimmune encephalomyelitis rat model. PET imaging was more sensitive than clinical symptoms for detecting inflammatory changes in the central nervous system.
Assuntos
Progressão da Doença , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Encefalomielite Autoimune Experimental/terapia , Tomografia por Emissão de Pósitrons , Amidas , Compostos de Anilina , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Isoquinolinas , Microglia/patologia , Monócitos/imunologia , Bainha de Mielina/metabolismo , Ratos , Estilbenos , Resultado do TratamentoRESUMO
Resveratrol is a major constituent of traditional Asian medicinal herbs and red wine and is suggested to be a potential antiatherosclerotic drug due to its proposed hypolipidemic, anti-inflammatory and antioxidative properties. The aim of this study was to evaluate whether resveratrol protects against atherosclerosis development in APOE*3-Leiden.CETP (E3L.CETP) mice and adds to the antiatherogenic effect of mild statin treatment, currently the most widely used antiatherogenic therapy. E3L.CETP mice were fed a cholesterol-rich diet without (control) or with resveratrol (0.01% w/w), atorvastatin (0.0027% w/w) or both for 14 weeks. During the study plasma lipid, inflammatory and oxidative stress parameters were determined. Resveratrol reduced atherosclerotic lesion area (-52%) in the aortic root, comparable to atorvastatin (-40%) and the combination of both drugs (-47%). The collagen/macrophage ratio in the atherosclerotic lesion, a marker of plaque stability, was increased by resveratrol (+108%), atorvastatin (+124%) and the combination (+154%). Resveratrol decreased plasma cholesterol levels (-19%) comparable to atorvastatin (-19%) and the combination (-22%), which was completely confined to (very)low-density lipoprotein cholesterol levels in all groups. Post hoc analyses showed that the antiatherogenic effect of atorvastatin could be explained by cholesterol lowering, while the antiatherosclerotic effect of resveratrol could be attributed to factors additional to cholesterol lowering. Markers of inflammation and oxidative stress were not different, but resveratrol improved macrophage function. We conclude that resveratrol potently reduces atherosclerosis development and induces a more stable lesion phenotype in E3L.CETP mice. However, under the experimental conditions tested, resveratrol does not add to the antiatherogenic effect of atorvastatin.
Assuntos
Aterosclerose/tratamento farmacológico , Ácidos Heptanoicos/farmacologia , Pirróis/farmacologia , Estilbenos/farmacologia , Animais , Aterosclerose/patologia , Atorvastatina , Biomarcadores/sangue , Colesterol na Dieta/administração & dosagem , LDL-Colesterol/sangue , Sinergismo Farmacológico , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , ResveratrolRESUMO
OBJECTIVE: Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD). APPROACH AND RESULTS: Mice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by -50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (-30%; -55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (-36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (-46%; -47%, P<0.01; -53%, P<0.001), atherosclerotic lesion area (-78%; -49%, P<0.01; -87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (-71%, P<0.01; -81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R(2)â=â0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R(2)â=â0.20, P<0.001). CONCLUSION: Niacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects. The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities. These data suggest that clinical beneficial effects of niacin are largely dependent on its ability to lower LDL-cholesterol on top of concomitant lipid-lowering therapy.
Assuntos
Apolipoproteína E3/genética , Aterosclerose/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/genética , Colesterol/sangue , Niacina/farmacologia , Animais , Transporte Biológico , Feminino , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , RNA Mensageiro/genética , Sinvastatina/farmacologia , Triglicerídeos/sangueRESUMO
OBJECTIVES: To validate near-infrared (NIR)-based optical spectroscopy measurements of hepatic fat content using a minimally invasive needle-like probe with integrated optical fibers, enabling real-time feedback during percutaneous interventions. The results were compared with magnetic resonance spectroscopy (MRS) as validation and with histopathology, being the clinical gold standard. Additionally, ex vivo magic angle spinning nuclear magnetic resonance spectroscopy and high-performance thin-layer chromatography were performed for comparison. MATERIALS AND METHODS: Ten mice were used for the study, of which half received a regular chow diet and the other half received a high-fat diet to induce obesity and hepatosteatosis. The mice were imaged with a clinical 3-Tesla MR to select a region of interest within the right and left lobes of the liver, where MRS measurements were acquired in vivo. Subsequently, optical spectra were measured ex vivo at the surface of the liver at 6 different positions immediately after resection. Additionally, hepatic fat was determined by magic angle spinning nuclear magnetic resonance spectroscopy and high-performance thin-layer chromatography. Histopathologic analyses were performed and used as the reference standard. Pearson correlation and linear regression analyses were performed to assess the correlation of the various techniques with NIR. A 1-way analysis of variance including post hoc Tukey multiple comparison tests was used to study the difference in fat estimation between the various techniques. RESULTS: For both the mice groups, the estimated fat fractions by the various techniques were significantly similar (P = 0.072 and 0.627 for chow diet and high-fat diet group, respectively). The Pearson correlation value between NIR and the other techniques for fat determination showed the same strong linear correlation (P above 0.990; P < 0.001), whereas for histopathologic analyses, which is a rather qualitative measure, the Pearson correlation value was slightly lower (P = 0.925, P < 0.001) . Linear regression coefficient computed to compare NIR with the other techniques resulted in values close to unity with MRS having the narrowest confidence interval (r = 0.935, 95% confidence interval: 0.860-1.009), demonstrating highly correlating results between NIR and MRS. CONCLUSIONS: NIR spectroscopy measurements from a needle-like probe with integrated optical fibers for sensing at the tip of the needle can quickly and accurately determine hepatic fat content during an interventional procedure and might therefore be a promising novel diagnosing tool in the clinic.
Assuntos
Adiposidade/fisiologia , Cromatografia Líquida de Alta Pressão/instrumentação , Tecnologia de Fibra Óptica/instrumentação , Fígado/fisiologia , Espectroscopia de Ressonância Magnética/instrumentação , Radiografia Intervencionista/instrumentação , Espectroscopia de Luz Próxima ao Infravermelho/instrumentação , Animais , Desenho de Equipamento , Análise de Falha de Equipamento , Fígado/diagnóstico por imagem , Fígado/patologia , Masculino , Camundongos , Camundongos Transgênicos , Agulhas , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Aliskiren is the first commercially available, orally active, direct renin inhibitor approved to treat hypertension. The renin-angiotensin system has been shown to be a significant contributor to the development of hypercholesterolemia-induced atherosclerosis. The aim of this study was to evaluate the antiatherosclerotic and plaque stabilization effects of aliskiren alone and in combination with atorvastatin. METHODS: APOE*3Leiden.CETP mice (nâ=â14-17/group) were fed a western-type diet (containing 0.25% cholesterol) alone or were treated with either aliskiren (15âmg/kg per day), atorvastatin (3.6âmg/kg per day) or a combination of aliskiren and atorvastatin. Effects on SBP, total cholesterol, inflammation markers and atherosclerotic size and composition were assessed. RESULTS: Aliskiren reduced SBP (-19%, Pâ<â0.001) and atorvastatin reduced total cholesterol (-24%, Pâ<â0.001). Atherosclerotic lesion area was reduced by aliskiren (-40%, Pâ<â0.01), atorvastatin (-61%, Pâ<â0.001) and the combination treatment (-69%, Pâ<â0.001). Aliskiren alone and together with atorvastatin decreased the number of T cells in the aortic root area (-60%, Pâ<â0.01; -41%, Pâ<â0.05), as well as macrophage (-64%, Pâ<â0.001; -72%, Pâ<â0.001) and necrotic area (-52%, Pâ=â0.071; -84%, Pâ<â0.001) in the lesion. Atorvastatin alone and together with aliskiren decreased monocyte adherence (-43%, Pâ<â0.05 and -51%, Pâ<â0.01) and monocyte chemoattractant protein-1 (both -36%, Pâ<â0.01). The combination treatment decreased the number of lesions (-17%, Pâ<â0.05) and E-selectin (-17%, Pâ<â0.05). CONCLUSION: Aliskiren inhibited atherosclerosis development and improved plaque stability alone and in combination with atorvastatin, possibly via a mechanism involving T cells. These results suggest a potential benefit of using aliskiren in a clinical setting, particularly in combination with statin treatment.