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1.
Am J Cardiovasc Drugs ; 21(3): 255-265, 2021 May.
Article in English | MEDLINE | ID: mdl-32929693

ABSTRACT

Lipoprotein(a) is a unique form of low-density lipoprotein. It is associated with a high incidence of premature atherosclerotic disease such as coronary artery disease, myocardial infarction, and stroke. Plasma levels of this lipoprotein and its activities are highly variable. This is because of a wide variability in the size of the apolipoprotein A moiety, which is determined by the number of repeats of cysteine-rich domains known as "kringles." Although the exact mechanism of lipoprotein(a)-induced atherogenicity is unknown, the lipoprotein has been found in the arterial walls of atherosclerotic plaques. It has been implicated in the formation of foam cells and lipid deposition in these plaques. Pharmacologic management of elevated levels of lipoprotein(a) with statins, fibrates, or bile acid sequestrants is ineffective. The newer and emerging lipid-lowering agents, such as the second-generation antisense oligonucleotides, cholesteryl ester transfer protein inhibitors, and proprotein convertase subtilisin/kexin type 9 inhibitors offer the most effective pharmacologic therapy.


Subject(s)
Dyslipidemias/drug therapy , Hypolipidemic Agents/therapeutic use , Lipoprotein(a)/blood , Atherosclerosis/pathology , Atherosclerosis/prevention & control , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol Ester Transfer Proteins/pharmacology , Humans , Hypolipidemic Agents/pharmacology , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/therapeutic use , PCSK9 Inhibitors , Plaque, Atherosclerotic/pathology , Plaque, Atherosclerotic/prevention & control , Proprotein Convertase 9/pharmacology , Risk Factors , Thrombosis/pathology , Thrombosis/prevention & control
2.
Biomed Pharmacother ; 110: 456-464, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30530048

ABSTRACT

10-Dehydrogingerdione is a novel cholesteryl ester transfer protein (CETP) inhibitor of natural origin. Some synthetic CETP inhibitors have recently been reported to suppress proprotein convertase subtilisin/kexin type 9 (PCSK9). Therefore, the present study aimed mainly to clarify the effect of 10-Dehydrogingerdione on cellular adhesion inflammatory molecules, platelet activation and endothelial dysfunction markers in addition to PCSK9 as compared to atorvastatin in dyslipidemic rabbits. Dyslipidemia was induced in 30 male rabbits, distributed in 3 equal groups through feeding dietary cholesterol (0.5% w/w) for 3 months. Two dyslipidemic groups were concurrently treated with either atorvastatin or 10-Dehydrogingerdione (10 mg/kg/ day, p.o) and dietary cholesterol. One additional group including 10 normal rabbits fed normal diet served as normal control (NC) group. Both 10-Dehydrogingerdione and atorvastatin significantly reduced serum CETP level and activity as well as PCSK9 and low density lipoprotein cholesterol (LDL-C) levels but increased high density lipoprotein cholesterol (HDL-C) levels as compared to dyslipidemic control (DC) rabbits (p < 0.001). Both treatments also induced a marked decrease in the interferon-gamma (IFN-γ), soluble CD40 ligand (sCD40L) and soluble P-selectin (sP-selectin) levels, inflammatory cell infiltration, as well as atherogenic and coronary risk indexes in addition to aortic atheromatous changes and intima/media ratio, respectively as compared to the DC group (p < 0.001). The reduction in these markers showed a significant correlation with PCSK9 suppression and CETP inhibitory effect. Interestingly, 10-Dehydrogingerdione exerted a greater ameliorative potential regarding these biomarkers than atorvastatin. Our findings suggest that 10-Dehydrogingerdione is a promising PCSK9 inhibitor with a significant protective value against many atherosclerotic risk factors.


Subject(s)
Cardiotonic Agents/therapeutic use , Dyslipidemias/metabolism , Endothelium, Vascular/metabolism , Guaiacol/analogs & derivatives , Inflammation Mediators/metabolism , Platelet Activation/drug effects , Animals , Cardiotonic Agents/pharmacology , Cholesterol Ester Transfer Proteins/pharmacology , Cholesterol Ester Transfer Proteins/therapeutic use , Dyslipidemias/prevention & control , Endothelium, Vascular/drug effects , Guaiacol/pharmacology , Guaiacol/therapeutic use , Inflammation Mediators/antagonists & inhibitors , Male , PCSK9 Inhibitors , Platelet Activation/physiology , Proprotein Convertase 9/metabolism , Rabbits
3.
J Lipid Res ; 52(12): 2323-2331, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21971713

ABSTRACT

The composition of lipoproteins and the association of proteins with various particles are of much interest in the context of cardiovascular disease. Here, we describe a technique for the multidimensional analysis of lipoproteins and their associated apolipoproteins. Plasma is separated by size exclusion chromatography (SEC), and fractions are analyzed by reverse-phase arrays. SEC fractions are spotted on nitrocellulose slides and incubated with different antibodies against individual apolipoproteins or antibodies against various apolipoproteins. In this way, tens of analytes can be measured simultaneously in 100 µl of plasma from a single SEC separation. This methodology is particularly suited to simultaneous analysis of multiple proteins that may change their distribution to lipoproteins or alter their conformation, depending on factors that influence circulating lipoprotein size or composition. We observed changes in the distribution of exchangeable apolipoproteins following addition of recombinant apolipoproteins or interaction with exogenous compounds. While the cholesteryl ester transfer protein (CETP)-dependent formation of pre-ß-HDL was inhibited by the CETP inhibitors torcetrapib and anacetrapib, it was not reduced by the CETP modulator dalcetrapib. This finding was elucidated using this technique.


Subject(s)
Blood Chemical Analysis/methods , Chromatography, Gel/methods , Lipoproteins/blood , Lipoproteins/isolation & purification , Protein Array Analysis/methods , Antibody Specificity , Artifacts , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol Ester Transfer Proteins/metabolism , Cholesterol Ester Transfer Proteins/pharmacology , High-Density Lipoproteins, Pre-beta/blood , High-Density Lipoproteins, Pre-beta/metabolism , Humans , Lipoproteins/immunology , Lipoproteins/metabolism , Quinolines/pharmacology , Reproducibility of Results
4.
Atherosclerosis ; 206(1): 153-8, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19345354

ABSTRACT

OBJECTIVE: Cholesteryl ester transfer protein (CETP) adversely affects the plasma lipoprotein profile by increasing VLDL-cholesterol and decreasing HDL-cholesterol. The relative contribution of either of these changes to atherosclerosis development is not known. We investigated to what extent the increase in VLDL-cholesterol can explain the atherogenic action of human CETP expression in APOE*3-Leiden (E3L) mice, a model for human-like lipoprotein metabolism. METHODS AND RESULTS: E3L mice and E3L.CETP mice were fed a low cholesterol (LC) diet, resulting in a 4-fold increased VLDL-cholesterol level as well as a 9-fold increased atherosclerotic lesion area in the aortic root in E3L.CETP mice compared to E3L-LC mice. E3L mice fed a high cholesterol (HC) diet to match the increased VLDL-cholesterol levels in E3L.CETP mice, displayed a similar atherosclerotic lesion area as observed in E3L.CETP mice. Hence, the CETP-induced raise in atherosclerosis can largely be explained by increased VLDL-cholesterol. Despite similar atherosclerosis development, E3L.CETP mice had lower HDL-cholesterol as compared to E3L-HC mice (-49%) indicating that the HDL-cholesterol lowering effect of CETP is unlikely to contribute to atherosclerosis development in this experimental setting. Remarkably, atherosclerotic lesions in CETP-expressing mice were enriched in collagen, suggesting a role of CETP or the diet in modifying lesion collagen content. CONCLUSIONS: In this experimental setting, the proatherogenic effect of CETP is largely explained by increased VLDL-cholesterol.


Subject(s)
Atherosclerosis/pathology , Cholesterol Ester Transfer Proteins/pharmacology , Cholesterol, HDL/blood , Cholesterol, VLDL/blood , Animals , Apolipoproteins E/genetics , E-Selectin/blood , Female , Fibrinogen/metabolism , Humans , Inflammation/blood , Mice , Serum Amyloid A Protein/metabolism
5.
Int J Pharm ; 358(1-2): 219-23, 2008 Jun 24.
Article in English | MEDLINE | ID: mdl-18448283

ABSTRACT

PURPOSE: Cyclosporine A (CsA), Rapamycin (RAPA), Tacrolimus (FK-506) and Mycophenolate mofetil (MMF) are immunosuppressants that are widely used in solid organ transplant patients. However, some of these drugs have been reported to cause dyslipidemia in patients. Our aim was to determine the effects of these drugs on in vitro cholesteryl ester transfer protein (CETP), hepatic lipase (HL) and lipoprotein lipase (LPL) activity within human plasma. METHODS: We measured CETP activity in human normolipidemic plasma with and without drug treatment, by measuring the incorporation of labeled cholesteryl ester into lipoproteins. To further confirm the result, we also measured recombinant CETP (rCETP) activity with and without drug treatment. We measured HL and LPL activity in post-heparin normal human plasma in the presence and absence of the drugs by measuring the release of fatty acids from radiolabeled triolein. RESULTS: We found an increase in CETP activity in human normolipidemic plasma and rCETP treated with CsA and RAPA. By contrast, CETP activity was not altered significantly in the presence of FK-506 and MMF. LPL activity in post-heparin normal human plasma was suppressed following the co-incubation with CsA, RAPA, FK-506 or MMF whereas HL activity remained unaffected. CONCLUSIONS: The increase in CETP activity and suppression in LPL activity following CsA and RAPA treatment observed in the present study may be associated with elevated LDL cholesterol levels and hypertriglyceridemia seen in patients administered these drugs.


Subject(s)
Cholesterol Ester Transfer Proteins/metabolism , Cyclosporine/pharmacology , Enzyme Inhibitors , Immunosuppressive Agents/pharmacology , Lipoprotein Lipase/antagonists & inhibitors , Sirolimus/pharmacology , Cholesterol Ester Transfer Proteins/blood , Cholesterol Ester Transfer Proteins/pharmacology , Fatty Acids/chemistry , Humans , Lipoprotein Lipase/blood , Liver/drug effects , Liver/enzymology , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/pharmacology , Recombinant Proteins/blood , Spectrometry, Fluorescence , Tacrolimus/pharmacology
6.
Shock ; 30(5): 590-5, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18391856

ABSTRACT

Mice expressing human cholesteryl ester transfer protein (huCETP) are more resistant to Escherichia coli bacterial wall LPS because death rates 5 days after intraperitoneal inoculation of LPS were higher in wild-type than in huCETP+/+ mice, whereas all huCETP+/+ mice remained alive. After LPS inoculation, plasma concentrations of TNF-alpha and IL-6 increased less in huCETP+/+ than in wild-type mice. LPS in vitro elicited lower TNF-alpha production by CETP expressing than by wild-type macrophages. In addition, TNF-alpha production by RAW 264.7 murine macrophages increased on incubation with LPS but decreased in a dose-dependent manner when human CETP was added to the medium. Human CETP in vitro enhanced the LPS binding to plasma high-density lipoprotein/low-density lipoprotein. The liver uptake of intravenous infused 14C-LPS from Salmonella typhimurium was greater in huCETP+/+ than in wild-type mice. Present data indicate for the first time that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators.


Subject(s)
Cholesterol Ester Transfer Proteins/physiology , Inflammation/genetics , Inflammation/mortality , Animals , Cells, Cultured , Cholesterol Ester Transfer Proteins/genetics , Cholesterol Ester Transfer Proteins/pharmacology , Cytokines/metabolism , Humans , Interleukin-6/blood , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacokinetics , Lipopolysaccharides/pharmacology , Liver/drug effects , Liver/metabolism , Macrophages/metabolism , Mice , Mice, Transgenic , Salmonella typhimurium/metabolism , Spleen/drug effects , Spleen/metabolism , Survival Rate , Tumor Necrosis Factor-alpha/blood
7.
Thromb Haemost ; 98(6): 1160-4, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18064308

ABSTRACT

Dyslipoproteinemia involving low levels of high density lipoprotein (HDL) is linked to venous thrombosis in young male adults and to recurrence of venous thrombosis in patients who have experienced a previous unprovoked venous thrombosis episode. Plasma cholesteryl ester transfer protein (CETP) modulates HDL metabolism and some lipoproteins can affect blood coagulation reactions with either procoagulant or anticoagulant effects. Hence, we evaluated relationships between the mass of CETP and blood coagulability in plasma samples from 39 normal healthy adults. For clotting initiated by dilute tissue factor or factor XIa, clotting times significantly correlated with CETP antigen levels. Thus, coagulation initiated by either the extrinsic or intrinsic coagulation pathway is positively correlated with CETP plasma levels. When added to plasma, a recombinant CETP preparation dose-dependently shortened factor Xa-1-stage clotting times, showing that it augmented procoagulant activity in plasma. In reaction mixtures containing purified factors Xa and Va and prothrombin, the recombinant CETP preparation dose-dependently increased prothrombin activation, suggesting it specifically enhances prothrombinase activity. Thus, our data highlight a previously unknown positive relationship between CETP plasma levels and blood coagulability that might relate to risks for thrombotic events.


Subject(s)
Blood Coagulation , Cholesterol Ester Transfer Proteins/blood , Adult , Blood Coagulation/drug effects , Cholesterol Ester Transfer Proteins/pharmacology , Dose-Response Relationship, Drug , Factor Va/metabolism , Factor XIa/metabolism , Factor Xa/metabolism , Female , Humans , Male , Partial Thromboplastin Time , Prothrombin/metabolism , Prothrombin Time , Recombinant Proteins/pharmacology , Reference Values , Thromboplastin/metabolism
8.
Clin Chim Acta ; 375(1-2): 92-8, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16859664

ABSTRACT

BACKGROUND: Cholesteryl ester transfer protein (CETP) is suggested to be involved in the cholesterol level in remnant like lipoprotein particles (RLP), but there is no direct evidence that CETP increases cholesterol-rich RLP in plasma. METHODS: Human plasma was incubated with or without HDL containing [(3)H]-labeled cholesteryl ester ([(3)H]CE), recombinant CETP or CETP inhibitors at 37 degrees C in vitro. RESULTS: The RLP-cholesterol (RLP-C) level increased time-dependently and the amount of RLP-C increase (DeltaRLP-C) by the incubation was positively correlated with triglyceride (TG) level in plasma (r=0.597, P=0.0070). [(3)H]CE in HDL was transferred to RLP fraction under 37 degrees C incubation, and the amount of [(3)H]CE transferred to RLP correlated significantly with DeltaRLP-C in plasma (r=0.611, P=0.0156). Human recombinant CETP enhanced the RLP-C increase, while CETP inhibitor JTT-705 and anti-human CETP monoclonal antibody inhibited both the RLP-C increase and [(3)H]CE transfer to RLP. On the other hand, an inhibition of lecithin: cholesterol acyltransferase (LCAT) did not affect the RLP-C increase. In triglyceride-rich lipoproteins (TRL) fraction, JTT-705 inhibited [(3)H]CE transfer to RLP more strongly than that to non-RLP. CONCLUSIONS: CETP promotes the formation of cholesterol-rich RLP through the transfer of CE from HDL to TRL and CETP inhibitors are useful to reduce RLP-C.


Subject(s)
Anticholesteremic Agents/pharmacology , Cholesterol Ester Transfer Proteins/pharmacology , Cholesterol/blood , Lipoproteins/blood , Sulfhydryl Compounds/pharmacology , Triglycerides/blood , Amides , Antibodies, Monoclonal/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol Ester Transfer Proteins/genetics , Dithionitrobenzoic Acid/pharmacology , Enzyme Inhibitors/pharmacology , Esters , Female , Humans , In Vitro Techniques , Male , Phosphatidylcholine-Sterol O-Acyltransferase/antagonists & inhibitors , Recombinant Proteins/pharmacology
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