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1.
PLoS Biol ; 17(12): e3000572, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31860674

RESUMO

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Doença das Coronárias/sangue , Hidroximetilglutaril-CoA Redutases/sangue , Lipoproteínas/sangue , Adolescente , Adulto , Alelos , Apolipoproteínas B/sangue , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , LDL-Colesterol/sangue , Estudos de Coortes , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/etiologia , Doença das Coronárias/genética , Feminino , Seguimentos , Variação Genética , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas/classificação , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Adulto Jovem
2.
J Microbiol Biotechnol ; 29(10): 1570-1579, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31474098

RESUMO

The fungal products dibenzodioxocinones promise a novel class of inhibitors against cholesterol ester transfer protein (CEPT). Knowledge as to their biosynthesis is scarce. In this report, we characterized four more dibenzodioxocinones, which along with a previously described member pestalotiollide B, delimit the dominant spectrum of secondary metabolites in P. microspora. Through mRNA-seq profiling in gα1Δ, a process that halts the production of the dibenzodioxocinones, a gene cluster harboring 21 genes including a polyketide synthase, designated as pks8, was defined. Disruption of genes in the cluster led to loss of the compounds, concluding the anticipated role in the biosynthesis of the chemicals. The biosynthetic route to dibenzodioxocinones was temporarily speculated. This study reveals the genetic basis underlying the biosynthesis of dibenzodioxocinone in fungi, and may facilitate the practice for yield improvement in the drug development arena.


Assuntos
Família Multigênica , Policetídeos/metabolismo , Xylariales/genética , Vias Biossintéticas , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Endófitos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Perfilação da Expressão Gênica , Família Multigênica/genética , Mutação , Paclitaxel/biossíntese , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Policetídeos/química , Xylariales/química , Xylariales/metabolismo
3.
Methodist Debakey Cardiovasc J ; 15(1): 39-46, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049148

RESUMO

High-density lipoprotein (HDL) is a protein-lipid nanoparticle that has predominately been characterized by its cholesterol concentration (HDL-C). Recent studies have challenged the presumed inverse association between HDL-C and cardiovascular events, suggesting a more U-shaped association. This has opened new opportunities to evaluate more novel measures of HDL metabolism, such as HDL particle number (HDL-P) and one of HDL's key functions, cholesterol efflux. Both HDL-P and cholesterol efflux are inversely associated with incident cardiovascular events and may perhaps be better targets for intervention. This review includes recent research on the emerging U-shaped association between HDL-C and cardiovascular events, recent observational studies related to HDL-P, and the effects of established and novel interventions on cholesterol efflux.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , HDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Animais , Anticolesterolemiantes/efeitos adversos , Transporte Biológico , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Proteínas de Transferência de Ésteres de Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Exercício Físico , Humanos , Comportamento de Redução do Risco , Resultado do Tratamento
6.
J Am Coll Cardiol ; 73(4): 477-487, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30704580

RESUMO

Cholesteryl ester transfer protein (CETP) facilitates exchange of triglycerides and cholesteryl ester between high-density lipoprotein (HDL) and apolipoprotein B100-containing lipoproteins. Evidence from genetic studies that variants in the CETP gene were associated with higher blood HDL cholesterol, lower low-density lipoprotein cholesterol, and lower risk of coronary heart disease suggested that pharmacological inhibition of CETP may be beneficial. To date, 4 CETP inhibitors have entered phase 3 cardiovascular outcome trials. Torcetrapib was withdrawn due to unanticipated off-target effects that increased risk of death, and major trials of dalcetrapib and evacetrapib were terminated early for futility. In the 30,000-patient REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, anacetrapib doubled HDL cholesterol, reduced non-HDL cholesterol by 17 mg/dl (0.44 mmol/l), and reduced major vascular events by 9% over 4 years, but anaceptrapib was found to accumulate in adipose tissue, and regulatory approval is not being sought. Therefore, despite considerable initial promise, CETP inhibition provides insufficient cardiovascular benefit for routine use.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , LDL-Colesterol/sangue , Ensaios Clínicos Fase III como Assunto , Humanos
7.
Am J Cardiovasc Drugs ; 19(3): 229-235, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30610681

RESUMO

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism and has presented an attractive target for drug development, primarily resting on the hope that CETP inhibition would reduce cardiovascular events through its ability to increase levels of high-density lipoprotein cholesterol (HDL-C). However, clinical development of CETP inhibitors has proven disappointing, with a spectrum of results spanning from evidence of harm, to futility, to only modest benefit in large-scale cardiovascular outcomes trials. A number of additional insights from genomic studies have suggested potential benefits from these agents in specific clinical settings. We review the current state of CETP inhibitors as an approach to targeting cardiovascular risk.


Assuntos
Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Doenças Cardiovasculares/etiologia , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangue , Desenvolvimento de Medicamentos , Humanos , Fatores de Risco
8.
Cardiol Rev ; 27(5): 242-248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30601160

RESUMO

Cholesterol metabolism and transport has been a major focus in cardiovascular disease risk modification over the past several decades. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been the most commonly used agents, with the greatest benefit in reducing both the primary and secondary risks of cardiovascular disease. However, heart disease remains the leading cause of death in both men and women in the United States. Further investigation and intervention are required to further reduce the risk for cardiovascular disease and cardiovascular-related deaths. This review will focus on high-density lipoprotein metabolism and transport, looking particularly at cholesteryl ester transfer protein (CETP) inhibitors. While studies of the other CETP inhibitors in its class have not shown a significant improvement in the prevention of primary or secondary cardiovascular risk, anacetrapib, the fourth and latest of the CETP inhibitors to be investigated, may be more promising.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Oxazolidinonas/uso terapêutico , Feminino , Humanos , Lipoproteínas HDL/metabolismo , Masculino
9.
Drug Metab Dispos ; 47(3): 227-233, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30567880

RESUMO

Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), associated with reduction in LDL cholesterol and increase in HDL cholesterol in hypercholesterolemic patients. Anacetrapib was not taken forward into filing/registration as a new drug for coronary artery diease, despite the observation of a ∼9% reduction in cardiovascular risk in a large phase III cardiovascular outcomes trial (REVEAL). Anacetrapib displayed no adverse effects throughout extensive preclinical safety evaluation, and no major safety signals were observed in clinical trials studying anacetrapib, including REVEAL. However, anacetrapib demonstrated a long terminal half-life in all species, thought to be due, in part, to distribution into adipose tissue. We sought to understand the dependence of anacetrapib's long half-life on adipose tissue and to explore potential mechanisms that might contribute to the phenomenon. In mice, anacetrapib localized primarily to the lipid droplet of adipocytes in white adipose tissue; in vitro, anacetrapib entry into cultured human adipocytes depended on the presence of a mature adipocyte and lipid droplet but did not require active transport. In vivo, the entry of anacetrapib into adipose tissue did not require lipase activity, as the distribution of anacetrapib into adipose was-not affected by systemic lipase inhibition using poloaxamer-407, a systemic lipase inhibitor. The data from these studies support the notion that the entry of anacetrapib into adipose tissue/lipid droplets does not require active transport, nor does it require mobilization or entry of fat into adipose via lipolysis.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Gotículas Lipídicas/metabolismo , Oxazolidinonas/farmacologia , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Linhagem Celular , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Meia-Vida , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Lipase/antagonistas & inibidores , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxazolidinonas/administração & dosagem , Oxazolidinonas/uso terapêutico , Poloxâmero/farmacologia , Distribuição Tecidual/efeitos dos fármacos
10.
Atherosclerosis ; 278: 286-298, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30347344

RESUMO

The cholesteryl ester transfer protein (CETP) system moves cholesteryl esters (CE) from high density lipoproteins (HDL) to lower density lipoproteins, i.e. very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) in exchange for triglycerides (TGs). This shuttle process will ultimately form complexes facilitating a bidirectional exchange of CE and TGs, the end process being CE delivery to catabolic sites. The CETP system is generally characteristic of higher animal species; lower species, not provided with this system, have higher and enlarged HDL enriched with apo E, suitable for tissue receptor interaction. Discovery of the CETP system has led to the development of agents interfering with CETP, thus elevating HDL-C and potentially preventing cardiovascular (CV) disease. Activation of CETP leads instead to reduced HDL-C levels, but also to an enhanced removal of CE from tissues. CETP antagonists are mainly small molecules (torcetrapib, anacetrapib, evacetrapib, dalcetrapib) and have provided convincing evidence of a HDL-C raising activity, but disappointing results in trials of CV prevention. In contrast, the CETP agonist probucol leads to HDL-C lowering followed by an increment of tissue cholesterol removal (reduction of xanthomas, xanthelasmas) and positive findings in secondary prevention trials. The drug has an impressive anti-inflammatory profile (markedly reduced interleukin-1ß expression). Newer agents, some of natural origin, have additional valuable pharmacodynamic properties. The pharmacological approach to the CETP system remains enigmatic, although the failure of CETP antagonists has dampened enthusiasm. Studies on the system, a crossroad for any investigation on cholesterol metabolism, have however provided crucial contributions and will still be confronting any scientist working on CV prevention.


Assuntos
Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/agonistas , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Benzodiazepinas/farmacologia , Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/fisiologia , HDL-Colesterol/metabolismo , Humanos , Lignanas/farmacologia , Lipoproteínas HDL/metabolismo , Lipoproteínas VLDL/metabolismo , Oxazolidinonas/farmacologia , Probucol/farmacologia , Quinolinas/farmacologia , Compostos de Sulfidrila/farmacologia , Triglicerídeos/metabolismo
11.
Nat Rev Nephrol ; 14(12): 727-749, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30361677

RESUMO

An increased risk of cardiovascular disease, independent of conventional risk factors, is present even at minor levels of renal impairment and is highest in patients with end-stage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease (CKD) or ESRD have a characteristic lipid pattern of hypertriglyceridaemia and low HDL cholesterol levels but normal LDL cholesterol levels. In the general population, a clear relationship exists between LDL cholesterol and major atherosclerotic events. However, in patients with ESRD, LDL cholesterol shows a negative association with these outcomes at below average LDL cholesterol levels and a flat or weakly positive association with mortality at higher LDL cholesterol levels. Overall, the available data suggest that lowering of LDL cholesterol is beneficial for prevention of major atherosclerotic events in patients with CKD and in kidney transplant recipients but is not beneficial in patients requiring dialysis. The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD provides simple recommendations for the management of dyslipidaemia in patients with CKD and ESRD. However, emerging data and novel lipid-lowering therapies warrant some reappraisal of these recommendations.


Assuntos
Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Insuficiência Renal Crônica/fisiopatologia , Produtos Biológicos/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Descoberta de Drogas , Dislipidemias/complicações , Dislipidemias/epidemiologia , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Fíbricos/uso terapêutico , Taxa de Filtração Glomerular , Humanos , Metabolismo dos Lipídeos , Guias de Prática Clínica como Assunto , Insuficiência Renal Crônica/complicações
12.
Atherosclerosis ; 278: 143-146, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30278356

RESUMO

Type 2 diabetes is a causal risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). While treatment with a statin reduces the risk of having an ASCVD event in all people, including those with type-2 diabetes, statin treatment also increases the likelihood of new onset diabetes when given to those with risk factors for developing diabetes. Treatment with the cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, reduces the risk of having a coronary event over and above that achieved with a statin. However, unlike statins, anacetrapib decreases the risk of developing diabetes. If the reduced risk of new-onset diabetes is confirmed in another CETP inhibitor outcome trial, there will be a case for considering the use of the combination of a statin plus a CETP inhibitor in high ASCVD-risk people who are also at increased risk of developing diabetes.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/complicações , Humanos , Oxazolidinonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
13.
Diabetes ; 67(12): 2494-2506, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213825

RESUMO

In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL's antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , Dieta Hiperlipídica , Fígado Gorduroso/genética , Resistência à Insulina/fisiologia , Animais , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Fígado Gorduroso/metabolismo , Camundongos , Camundongos Transgênicos , Oxazolidinonas/farmacologia
14.
Int J Pharm ; 549(1-2): 388-396, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30107219

RESUMO

CKD-519, a potent cholesteryl ester transfer protein (CETP) inhibitor, is a clinical candidate being developed for the treatment of dyslipidemia. It is considered a Biopharmaceutical Classification System II compound with low solubility and high permeability. The objective of this study was to develop early formulations focusing on the dissolution rate of the compound to achieve dose-dependent exposure. High performance formulation strategies including solid dispersion (SD) and a self-microemulsifying drug delivery system (SMEDDS) were investigated and their in vivo and in vitro correlations were also evaluated in monkeys along with dose optimization in human volunteers. The SD granules were prepared in a fluid bed granulator using microcrystalline cellulose and mannitol as carriers. Poloxamer 407 and Eudragit E PO were each found to be a suitable solubilizing agent and polymer for the improvement of the CKD-519 dissolution rate. Pharmacokinetic studies in monkeys showed that the SD tablets exhibited better absorption than the SMEDDS in a dose-dependent manner from 1.5 mg to 100 mg. The mannitol-based SD tablet formulations were bioequivalent. However, pharmacokinetics studies in humans showed that the dose was saturable above 100 mg of CKD-519. This study was performed to determine how to develop early formulations for clinical studies and to identify rational formulation development strategies for CKD-519 to establish the pharmaceutical proof-of-concept in humans.


Assuntos
Anticolesterolemiantes/administração & dosagem , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Desenvolvimento de Medicamentos/métodos , Hidrocarbonetos Fluorados/administração & dosagem , Oxazóis/administração & dosagem , Administração Oral , Adulto , Animais , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacocinética , Disponibilidade Biológica , Celulose/química , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Método Duplo-Cego , Portadores de Fármacos , Composição de Medicamentos , Excipientes/química , Feminino , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacocinética , Macaca mulatta , Masculino , Manitol/química , Pessoa de Meia-Idade , Modelos Biológicos , Oxazóis/química , Oxazóis/farmacocinética , Permeabilidade , Poloxâmero/química , Ácidos Polimetacrílicos/química , Estudo de Prova de Conceito , Solubilidade , Comprimidos , Adulto Jovem
15.
Atherosclerosis ; 276: 39-43, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30029099

RESUMO

Plasma HDL levels have an inverse relationship to coronary artery disease (CAD) risk, which led to the idea that increasing HDL levels therapeutically would ameliorate atherosclerosis. Human genetic deficiency of CETP caused markedly elevated HDL and moderately reduced non-HDL cholesterol levels, suggesting that CETP inhibitors might produce cardiovascular benefit. The CETP inhibitor anacetrapib reproduced the phenotype of homozygous CETP deficiency and showed a highly significant benefit for CAD in the REVEAL trial. However, the magnitude of this effect was moderate, and the mechanism of benefit remains unclear. Insights into the mechanisms underlying macrophage cholesterol efflux and reverse cholesterol transport have come from monogenic human disorders and transgenic mouse studies. In particular, the importance of the ATP binding cassette transporters ABCA1 and ABCG1 in promoting cholesterol efflux from myeloid and other hematopoietic cells has been shown and linked to aberrant myelopoiesis and macrophage inflammation. Recent studies have shown that myeloid deficiency of ABCA1 and ABCG1 leads to macrophage and neutrophil inflammasome activation, which in turn promotes atherosclerotic plaque development and notably the formation of neutrophil extracellular traps (NETs) in plaques. In addition, clonal hematopoiesis has emerged as an important CAD risk factor, likely involving macrophage inflammation and inflammasome activation. Further elucidation of the mechanisms linking plaque accumulation of cholesterol and oxidized lipids to myeloid cell inflammation may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for CAD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Inflamação/tratamento farmacológico , Lipoproteínas HDL/sangue , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/imunologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/imunologia , Inibidores Enzimáticos/uso terapêutico , Predisposição Genética para Doença , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/sangue , Inflamação/genética , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fenótipo , Regulação para Cima
16.
Clin Pharmacol Ther ; 104(2): 297-300, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29901215

RESUMO

Inhibitors of cholesteryl ester transfer protein (CETP) were developed due to their ability to raise HDL-C levels. Preclinical studies demonstrated favorable effects on atherosclerotic plaque with CETP inhibitory approaches in animal models. While these agents raise HDL-C and lower LDL-C, most have not proven to reduce cardiovascular event rates in large outcome trials. The state of opinion after all of these clinical trials is reviewed.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , HDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Animais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Proteínas de Transferência de Ésteres de Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/genética , Predisposição Genética para Doença , Humanos , Hipolipemiantes/efeitos adversos , Análise da Randomização Mendeliana , Medição de Risco , Fatores de Risco , Resultado do Tratamento
17.
Appl Biochem Biotechnol ; 186(4): 805-815, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29740798

RESUMO

Platelet markers [soluble p selectin (sP-selectin) and soluble CD40 ligand (sCD40L)] are associated with platelet activation and cardiovascular risk. Both policosanol and 10-dehydrogingerdione are natural products with proven CETP inhibitory and antiatherogenic effects. Present work aimed mainly to investigate the levels of platelet activation biomarkers in the serum of dyslipidemic rabbits and the potential of these phytochemicals either alone or in a combination form to protect against atherogenicity. Additionally, this work clarified their effect on PCSK9, a key player in atherosclerosis progression. Daily administration of policosanol and/or 10-dehydrogingerdione at a dose level 10 mg/kg bw resulted in a CETP inhibitory activity, increasing HDL-C level. This protective effect was associated with improvement in lipid profile components and a reduction in PCSK9 level. Interestingly, this combination strengthened the CETP inhibitory activity of these phytochemicals, leading to a greater increase in serum HDL-C level than monotherapy. However, this combination did not enhance the reduction in PCSK9 level. Both drugs also decreased platelet activation and inflammation markers such as sCD40L, sP-selectin, and interferon-gamma (IFN-γ), and their combination showed a synergistic effect. Therefore, such phytochemicals may be regarded as promising agents in the protection against atherothrombosis risk.


Assuntos
Plaquetas/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Álcoois Graxos/farmacologia , Guaiacol/análogos & derivados , Compostos Fitoquímicos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/farmacologia , Animais , Guaiacol/farmacologia , Masculino , Coelhos
18.
Clin Pharmacokinet ; 57(11): 1359-1367, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29730761

RESUMO

The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/farmacocinética , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Disponibilidade Biológica , Sistema Cardiovascular/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Humanos , Compostos de Sulfidrila/uso terapêutico
19.
Cardiol Clin ; 36(2): 299-310, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29609759

RESUMO

Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from the nonatherogenic high density lipoprotein (HDL) fraction to potentially proatherogenic non-HDL fractions. Inhibition of CETP reduces the concentration of non-HDL cholesterol, enhances HDL functionality, and increases the concentration of HDL cholesterol and apoA-I. Despite an absence of benefit in earlier trials of CETP inhibition, the REVEAL trial has shown that treatment with the CETP inhibitor anacetrapib reduces the risk of having a coronary event in high-risk, statin-treated patients.


Assuntos
Anticolesterolemiantes/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Doença das Coronárias , Proteínas de Transferência de Ésteres de Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Saúde Global , Humanos , Incidência , Prognóstico
20.
J Lipid Res ; 59(5): 772-783, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29487091

RESUMO

Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/química , Humanos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química
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