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1.
Metabolism ; 97: 57-67, 2019 08.
Article in English | MEDLINE | ID: mdl-31153978

ABSTRACT

BACKGROUND: Muscle atrophy is defined as decreased muscle mass, associated with aging as well as with various chronic diseases and is a fundamental cause of frailty, functional decline and disability. Frailty represents a huge potential public health issue worldwide with high impact on healthcare costs. A major clinical issue is therefore to devise new strategies preventing muscle atrophy. In this study, we tested the efficacy of Vital01, a novel oral nutritional supplement (ONS), on body weight and muscle mass using a caloric restriction-induced mouse model for muscle atrophy. METHODS: Mice were calorically restricted for 2 weeks to induce muscle atrophy: one control group received 60% kcal of the normal chow diet and one intervention group received 30% kcal chow and 30 kcal% Vital01. The effects on body weight, lean body mass, muscle histology and transcriptome were assessed. In addition, the effects of Vital01, in mice with established muscle atrophy, were assessed and compared to a standard ONS. To this end, mice were first calorically restricted on a 60% kcal chow diet and then refed with either 100 kcal% chow, a mix of Vital01 (receiving 60% kcal chow and 40 kcal% Vital01) or with a mix of standard, widely prescribed ONS (receiving 60 kcal% chow and 40 kcal% Fortisip Compact). RESULTS: Vital01 attenuated weight loss (-15% weight loss for Vital01 vs. -25% for control group, p < 0.01) and loss of muscle mass (Vital01 with -13%, -12% and -18%, respectively, for gastrocnemius, quadriceps and tibialis vs. 25%, -23% and -28%, respectively, for control group, all p < 0.05) and also restored body weight, fat and muscle mass more efficiently when compared to Fortisip Compact. As assessed by transcriptome analysis and Western blotting of key proteins (e.g. phospoAKT, mTOR and S6K), Vital01 attenuated the catabolic and anabolic signaling pathways induced by caloric restriction and modulated inflammatory and mitochondrial pathways. In addition, Vital01 affected pathways related to matrix proteins/collagens homeostasis and tended to reduce caloric restriction-induced collagen fiber density in the quadriceps (with -27%, p = 0.051). CONCLUSIONS: We demonstrate that Vital01 preserves muscle mass in a calorically restricted mouse model for muscle atrophy. Vital01 had preventive effects when administered during development of muscle atrophy. Furthermore, when administered in a therapeutic setting to mice with established muscle atrophy, Vital01 rapidly restored body weight and accelerated the recurrence of fat and lean body mass more efficiently than Fortisip Compact. Bioinformatics analysis of gene expression data identified regulatory pathways that were specifically influenced by Vital01 in muscle.


Subject(s)
Body Weight/physiology , Muscle, Skeletal/physiology , Muscular Atrophy/physiopathology , Animals , Body Composition/physiology , Body Mass Index , Caloric Restriction/methods , Dietary Supplements , Disease Models, Animal , Energy Intake/physiology , Male , Mice , Mice, Inbred C57BL , Weight Loss/physiology
2.
Transpl Int ; 27(12): 1272-84, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25082296

ABSTRACT

The uremia-induced inflammatory environment in end-stage renal disease (ESRD) patients is associated with premature T-cell aging resulting in a defective T-cell immunity. As kidney transplantation (KTx) reduces the pro-inflammatory environment, we hypothesized that KTx would rejuvenate the aged T-cell system. As aging parameters, we determined in 70 KTx recipients the differentiation status by immunophenotyping, thymic output by the T-cell receptor excision circle (TREC) content together with CD31(+) naïve T-cell numbers and the relative telomere length (RTL) as a measure for proliferative history at pre-KTx, 3, 6 and 12 months post-KTx. In addition, T-cell function was determined by measuring the proliferative capacity and percentages of cytokine-producing cells. Directly post-KTx, memory T-cell numbers were diminished but restored to pre-KTx values at 12 months, except for CD4(+) EM T cells. The RTL of (memory) CD4(+) and CD8(+) T cells did not change. In contrast, TREC content and CD31(+) naïve T-cell numbers were stable post-KTx although the RTL of naïve CD4(+) and CD8(+) T cells decreased implying homeostatic proliferation of naïve cells, in response to a temporary decrease in memory cells. The T-cell function was not improved post-KTx. Our findings demonstrate that the uremia-associated aged phenotype is stably imprinted in the T-cell system and not reversed by KTx.


Subject(s)
Kidney Transplantation , T-Lymphocyte Subsets/immunology , Uremia/immunology , Adult , Aged , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/ultrastructure , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/ultrastructure , Cellular Senescence/immunology , Female , Humans , Immunologic Memory/immunology , Male , Middle Aged , Renal Replacement Therapy , Telomere Homeostasis , Thymus Gland/immunology , Uremia/surgery , Uremia/therapy
3.
Immun Ageing ; 9(1): 19, 2012 Sep 12.
Article in English | MEDLINE | ID: mdl-22971545

ABSTRACT

BACKGROUND: End-stage renal disease (ESRD) patients treated with renal replacement therapy (RRT) have premature immunologically aged T cells which may underlie uremia-associated immune dysfunction. The aim of this study was to investigate whether uremia was able to induce premature ageing of the T cell compartment. For this purpose, we examined the degree of premature immunological T cell ageing by examining the T cell differentiation status, thymic output via T cell receptor excision circle (TREC) content and proliferative history via relative telomere length in ESRD patients not on RRT. RESULTS: Compared to healthy controls, these patients already had a lower TREC content and an increased T cell differentiation accompanied by shorter telomeres. RRT was able to enhance CD8+ T cell differentiation and to reduce CD8+ T cell telomere length in young dialysis patients. An increased differentiation status of memory CD4+ T cells was also noted in young dialysis patients. CONCLUSION: Based on these results we can conclude that uremia already causes premature immunological ageing of the T cell system and RRT further increases immunological ageing of the CD8+ T cell compartment in particular in young ESRD patients.

4.
Transplantation ; 94(1): 63-9, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22691956

ABSTRACT

BACKGROUND: End-stage renal disease (ESRD) is associated with T-cell dysregulation, leading to a variable degree of lymphopenia and increased T-cell differentiation. This may cause a relevant reduction in T-cell immunity, yielding a lowered risk for acute rejection (AR) of kidney allografts. METHODS: Before kidney transplantation, circulating CD4 and CD8 T-cell differentiation was established by determining the frequency of naive T cells, central memory and effector memory T cells, and the highly differentiated CD8 Temra cells. In addition, the frequency of differentiated T cells without expression of the costimulatory molecule CD28 was measured. RESULTS: In 47 patients of the 185 patients included, a biopsy-proven AR occurred. Compared with healthy controls, T cells of patients with ESRD were significantly more differentiated. Patients with AR showed the least signs of T-cell dysregulation with significantly more T cells, more naive T cells, and less terminal differentiation of memory T cells compared with nonrejecting patients. After multivariate analysis, only the frequency of terminally differentiated CD8 Temra cells (per percent, 4% decrease of risk [P=0.006]; per tertile, 34% decrease in risk [P=0.002]) and the number of human leukocyte antigen mismatches (per mismatch, 33% [P=0.005]) predicted the risk for AR. Functional analysis showed that CD8 Temra cells have a highly proinflammatory and cytotoxic profile. In vitro T-cell proliferation assays did not reveal a suppressor function of these cells. CONCLUSIONS: Advanced ESRD-related T-cell dysregulation that is associated with a relative increase of terminally differentiated CD8 Temra cells protects against AR after kidney transplantation.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Graft Rejection/etiology , Kidney Transplantation/adverse effects , Acute Disease , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation , Female , Histocompatibility Testing , Humans , Kidney Failure, Chronic/immunology , Kidney Transplantation/mortality , Lymphocyte Activation , Male , Middle Aged , Proportional Hazards Models , Risk Factors , Transplantation, Homologous
5.
Kidney Int ; 80(2): 208-17, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21525849

ABSTRACT

Progressive loss of renal function is associated with a dysregulation of circulating T cells that may underlie their impaired T-cell immunity. Here we tested whether end-stage renal disease (ESRD)-related T-cell alterations are compatible with the concept of premature immunological aging. Younger patients (25-45 years old) with ESRD were found to resemble older healthy controls (60-80 years old) as they had a significant loss of naive T cells and a relative increase of memory T cells showing progressive terminal differentiation. A significant decrease in the content of T-cell receptor excision circles and telomere length in patients with ESRD confirmed these phenotypic data. The loss of naive T cells in patients with ESRD was associated with an excessive age-related decrease of recent thymic emigrants, indicating a premature decline in thymic function. Additionally, increased homeostatic proliferation of naive T cells was found in patients with ESRD, similar to that of older healthy individuals, with an increased susceptibility for activation-induced apoptosis. Therefore, both decreased thymic output and increased susceptibility of naive T cells for apoptosis may play a role in the loss of naive T cells in ESRD patients. Thus, our results are compatible with premature aging of the T-cell system of patients with ESRD comparable with that of healthy individuals 20-30 years older.


Subject(s)
Cellular Senescence/immunology , Kidney Failure, Chronic/immunology , T-Lymphocytes/pathology , Adult , Age Factors , Aged , Aged, 80 and over , Apoptosis/immunology , Blood Cells , CD4 Lymphocyte Count , Case-Control Studies , Humans , Middle Aged , Thymus Gland
6.
Immun Ageing ; 8(1): 2, 2011 Jan 08.
Article in English | MEDLINE | ID: mdl-21214947

ABSTRACT

The age- and cytomegalovirus (CMV)-seropositivity-related changes in subsets and differentiation of circulating T cells were investigated in end-stage renal disease (ESRD) patients (n = 139) and age-matched healthy individuals. The results show that CMV-seropositivity is associated with expansion of both CD4+ and CD8+ memory T cells which is already observed in young healthy individuals. In addition, CMV-seropositive healthy individuals have a more differentiated memory T cell profile. Only CMV-seropositive healthy individuals showed an age-dependent decrease in CD4+ naïve T cells. The age-related decrease in the number of CD8+ naïve T cells was CMV-independent. In contrast, all ESRD patients showed a profound naïve T-cell lymphopenia at every decade. CMV-seropositivity aggravated the contraction of CD4+ naïve T cells and increased the number of differentiated CD4+ and CD8+ memory T cells. In conclusion, CMV-seropositivity markedly alters the homeostasis of circulating T cells in healthy individuals and aggravates the T cell dysregulation observed in ESRD patients.

7.
Nephrol Dial Transplant ; 25(11): 3640-6, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20400452

ABSTRACT

BACKGROUND: Cytomegalovirus seropositivity is associated with an increased risk for cardiovascular disease in end-stage renal disease (ESRD) patients. Circulating pro-inflammatory CD4posCD28null T cells are expanded in cytomegalovirus-seropositive ESRD patients and potentially could mediate atherosclerotic plaque instability and rupture. METHODS: In this study, we tested the hypothesis that increased numbers of circulating CD4posCD28null T cells may represent a risk factor for cardiovascular disease in ESRD patients. Prospectively collected data from 240 cytomegalovirus-seropositive stable ESRD patients were analysed. RESULTS: Traditional cardiovascular risk factors (age, smoking, hypercholesterolaemia and diabetes mellitus) and the percentage and absolute number of CD4posCD28null T cells were significantly associated with the presence of atherosclerotic disease, after univariate and multivariate statistical analysis. An ~2-3-fold increase in the prevalence of atherosclerotic disease was noted between patients with the highest and lowest number of CD4posCD28null cells. CD8posCD28null T-cell populations were also significantly expanded in cytomegalovirus-seropositive ESRD patients and closely correlated with the number of CD4posCD28null T cells. However, this cell population was not related to an increased prevalence of cardiovascular disease. CONCLUSIONS: Cytomegalovirus-seropositive ESRD patients may have substantially increased numbers of circulating pro-inflammatory CD4posCD28null T cells that are independently associated with the presence of atherosclerotic disease. The expansion of these cells may therefore represent a novel non-traditional cardiovascular risk factor for ESRD patients.


Subject(s)
CD28 Antigens/analysis , CD4 Antigens/analysis , Cardiovascular Diseases/etiology , Kidney Failure, Chronic/complications , T-Lymphocytes/physiology , Adult , Aged , Aged, 80 and over , Atherosclerosis/etiology , Atherosclerosis/immunology , Cytomegalovirus Infections/complications , Female , Humans , Interferon-gamma/biosynthesis , Kidney Failure, Chronic/immunology , Male , Middle Aged , Risk Factors , Tumor Necrosis Factor-alpha/biosynthesis
8.
PLoS One ; 3(4): e2013, 2008 Apr 23.
Article in English | MEDLINE | ID: mdl-18431494

ABSTRACT

BACKGROUND: Neutrophils depend mainly on glycolysis for their energy provision. Their mitochondria maintain a membrane potential (Deltapsi(m)), which is usually generated by the respiratory chain complexes. We investigated the source of Deltapsi(m) in neutrophils, as compared to peripheral blood mononuclear leukocytes and HL-60 cells, and whether neutrophils can still utilise this Deltapsi(m) for the generation of ATP. METHODS AND PRINCIPAL FINDINGS: Individual activity of the oxidative phosphorylation complexes was significantly reduced in neutrophils, except for complex II and V, but Deltapsi(m) was still decreased by inhibition of complex III, confirming the role of the respiratory chain in maintaining Deltapsi(m). Complex V did not maintain Deltapsi(m) by consumption of ATP, as has previously been suggested for eosinophils. We show that complex III in neutrophil mitochondria can receive electrons from glycolysis via the glycerol-3-phosphate shuttle. Furthermore, respiratory supercomplexes, which contribute to efficient coupling of the respiratory chain to ATP synthesis, were lacking in neutrophil mitochondria. When HL-60 cells were differentiated to neutrophil-like cells, they lost mitochondrial supercomplex organisation while gaining increased aerobic glycolysis, just like neutrophils. CONCLUSIONS: We show that neutrophils can maintain Deltapsi(m) via the glycerol-3-phosphate shuttle, whereby their mitochondria play an important role in the regulation of aerobic glycolysis, rather than producing energy themselves. This peculiar mitochondrial phenotype is acquired during differentiation from myeloid precursors.


Subject(s)
Electron Transport Complex III/metabolism , Membrane Potential, Mitochondrial , Neutrophils/drug effects , Neutrophils/enzymology , Adenosine Triphosphate/metabolism , Cell Differentiation/drug effects , Cell Separation , Electron Transport/drug effects , HL-60 Cells , Humans , Lactic Acid/biosynthesis , Membrane Potential, Mitochondrial/drug effects , Neutrophils/cytology , Oxidative Phosphorylation/drug effects , Phenotype , Phosphates/metabolism , Uncoupling Agents/pharmacology
9.
Eur J Pharmacol ; 539(1-2): 89-98, 2006 Jun 06.
Article in English | MEDLINE | ID: mdl-16687134

ABSTRACT

1-{7-[(1-(3,5-Diethoxyphenyl)-3-{[(3,5-difluorophenyl)(ethyl)amino]carbonyl}-4-oxo-1,4-dihydroquinolin-7-yl)oxy]heptyl}-1-methylpiperidinium bromide, R-146224, is a potent, specific ileum apical sodium-dependent bile acid transporter (ASBT) inhibitor; concentrations required for 50% inhibition of [3H]taurocholate uptake in human ASBT-expressing HEK-293 cells and hamster ileum tissues were 0.023 and 0.73 microM, respectively. In bile-fistula rats, biliary and urinary excretion 48 h after 10 mg/kg [14C]R-146224, were 1.49+/-1.75% and 0.14+/-0.05%, respectively, demonstrating extremely low absorption. In hamsters, R-146224 dose-dependently reduced gallbladder bile [3H]taurocholate uptake (ED50: 2.8 mg/kg). In basal diet-fed hamsters, 14-day 30-100 mg/kg R-146224 dose-dependently reduced serum total cholesterol (approximately 40%), high density lipoprotein (HDL) cholesterol (approximately 37%), non-HDL cholesterols (approximately 20%), and phospholipids (approximately 20%), without affecting serum triglycerides, associated with reduced free and esterified liver cholesterol contents. In normocholesterolemic cynomolgus monkeys, R-146224 specifically reduced non-HDL cholesterol. In human ileum specimens, R-146224 dose-dependently inhibited [3H]taurocholate uptake. Potent non-systemic ASBT inhibitor R-146224 decreases bile acid reabsorption by inhibiting the ileal bile acid active transport system, resulting in hypolipidemic activity.


Subject(s)
Anticholesteremic Agents/pharmacology , Bile Acids and Salts/metabolism , Cholesterol/blood , Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors , Piperidines/pharmacology , Quinolines/pharmacology , Sodium/physiology , Symporters/antagonists & inhibitors , Animals , Anticholesteremic Agents/pharmacokinetics , Cell Line , Cricetinae , Humans , Ileum/drug effects , Ileum/metabolism , In Vitro Techniques , Macaca fascicularis , Male , Membrane Transport Proteins/biosynthesis , Membrane Transport Proteins/genetics , Mesocricetus , Organic Anion Transporters, Sodium-Dependent/biosynthesis , Organic Anion Transporters, Sodium-Dependent/genetics , Piperidines/pharmacokinetics , Quinolines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Symporters/biosynthesis , Symporters/genetics , Taurocholic Acid/antagonists & inhibitors , Taurocholic Acid/metabolism
10.
Biochim Biophys Acta ; 1741(1-2): 95-102, 2005 Jun 30.
Article in English | MEDLINE | ID: mdl-15955452

ABSTRACT

The hallmark of fibrosis is the excessive accumulation of collagen. The deposited collagen contains increased pyridinoline cross-link levels due to an overhydroxylation of lysine residues within the collagen telopeptides. Lysyl hydroxylase 2b (LH2b) is the only lysyl hydroxylase consistently up-regulated in several forms of fibrosis, suggesting that an enhanced LH2b level is responsible for the overhydroxylation of collagen telopeptides. The present paper reports the effect of profibrotic cytokines on the expression of collagen, lysyl hydroxylases and lysyl oxidase in normal human skin fibroblasts, as well as the effect on pyridinoline formation in the deposited matrix. All three isoforms of TGF-beta induce a substantial increase in LH2b mRNA levels, also when expressed relatively to the mRNA levels of collagen type I alpha2 (COL1A2). The TGF-beta isoforms also clearly influence the collagen cross-linking pathway, since higher levels of pyridinoline cross-links were measured. Similar stimulatory effects on LH2b/COL1A2 mRNA expression and pyridinoline formation were observed for IL-4, activin A, and TNF-alpha. An exception was BMP-2, which has no effect on LH2b/COL1A2 mRNA levels nor on pyridinoline formation. Our data show for the first time that two processes, i.e., up-regulation of LH2b mRNA levels and increased formation of pyridinoline cross-links, previously recognized to be inherent to fibrotic processes, are induced by various profibrotic cytokines.


Subject(s)
Amino Acids/chemistry , Cross-Linking Reagents/pharmacology , Cytokines/pharmacology , Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/metabolism , Activins/pharmacology , Cells, Cultured , Collagen Type I/metabolism , Fibroblasts/drug effects , Fibroblasts/enzymology , Fibroblasts/metabolism , Fibrosis/pathology , Gene Expression Regulation, Enzymologic , Humans , Inhibin-beta Subunits/pharmacology , Interleukin-4/pharmacology , Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/genetics , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Isoforms/pharmacology , RNA, Messenger/metabolism , Skin/cytology , Time Factors , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Up-Regulation
11.
Circ Res ; 96(12): e92-e101, 2005 Jun 24.
Article in English | MEDLINE | ID: mdl-15933268

ABSTRACT

Apoptosis-inducing factor (AIF), or programmed cell death 8 (Pdcd8), is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal apoptosis induced by oxidative stress. Conversely, in vitro, AIF has been demonstrated to have a proapoptotic role when, on induction of the mitochondrial death pathway, AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. To determine the role of AIF in myocardial apoptotic processes, we examined cardiomyocytes from an AIF-deficient mouse mutant, Harlequin (Hq). Hq mutant cardiomyocytes demonstrated increased sensitivity to H2O2-induced cell death. Further, Hq hearts subjected to ischemia/reperfusion revealed more cardiac damage and, unlike wild-type mice, the amount of damage increased with the age of the animal. Aortic banding caused enhanced hypertrophy, increased cardiomyocyte apoptotic and necrotic cell death, and accelerated progression toward maladaptive left ventricular remodeling in Hq mutant mice compared with wild-type counterparts. These findings correlated with a reduced capacity of subsarcolemmal mitochondria from Hq mutant hearts to scavenge free radicals. Together, these data demonstrate a critical role for AIF as a cardiac antioxidant in the protection against oxidative stress-induced cell death and development of heart failure induced by pressure overload.


Subject(s)
Apoptosis , Flavoproteins/physiology , Heart Failure/etiology , Membrane Proteins/physiology , Myocardium/pathology , Oxidative Stress , Animals , Apoptosis Inducing Factor , Biomechanical Phenomena , Cells, Cultured , Down-Regulation , Female , Fibrosis , Flavoproteins/genetics , Hydrogen Peroxide/pharmacology , Male , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Mutant Strains , Myocardial Reperfusion Injury/etiology , Myocardium/metabolism , RNA, Small Interfering/pharmacology , Ventricular Remodeling
12.
J Cardiovasc Pharmacol ; 45(1): 53-60, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15613980

ABSTRACT

The present study was designed to investigate the lipid-lowering properties and mechanisms of action of a new HMG-CoA reductase inhibitor, rosuvastatin, in female ApoE*3-Leiden transgenic mice. Mice received a high fat/cholesterol (HFC) diet containing either rosuvastatin (0 [control], 0.00125%, 0.0025%, or 0.005% [w/w]) or 0.05% (w/w) lovastatin. The highest dose of rosuvastatin reduced plasma cholesterol and triglyceride levels by 39% and 42%, respectively, compared with the HFC control. Lovastatin had no effect on plasma cholesterol and triglyceride levels. In ApoE*3-Leiden mice on a chow diet, rosuvastatin (0.005% [w/w]) decreased plasma cholesterol levels by 35% without having an effect on triglyceride levels. On a chow diet, expression of genes involved in cholesterol biosynthesis and uptake in the liver was increased by rosuvastatin. Further mechanistic studies in HFC-fed mice showed that rosuvastatin treatment resulted in decreased hepatic VLDL-triglyceride and VLDL-apolipoprotein B production. VLDL lipid composition remained unchanged, indicating a reduction in the number of VLDL particles secreted. Lipolytic activity and expression of genes involved in cholesterol and triglyceride synthesis and beta-oxidation of fatty acids in the liver were not affected by rosuvastatin treatment, and hepatic lipid content did not change. However, activity of hepatic diacylglycerol acyltransferase was significantly decreased by 25% after rosuvastatin treatment. Moreover, biliary excretion of cholesterol, phospholipids, and bile acids was increased during treatment. The results indicate that rosuvastatin treatment in ApoE*3-Leiden mice on a HFC diet leads to redistribution of cholesterol and triglycerides in the body, both by reduced hepatic VLDL production and triglyceride synthesis and by enhanced hepatobiliary removal of cholesterol, bile acids, and phospholipids, resulting in substantial reductions in plasma cholesterol and triglyceride levels.


Subject(s)
Apolipoproteins E/genetics , Cholesterol, VLDL/biosynthesis , Cholesterol/metabolism , Fluorobenzenes/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Triglycerides/metabolism , Animals , Apolipoprotein E3 , Apolipoproteins B/biosynthesis , Bile/metabolism , Bile Acids and Salts/metabolism , Cholesterol/blood , Cholesterol/genetics , Cholesterol, VLDL/blood , Chromatography, High Pressure Liquid , Feces/chemistry , Female , Liver/metabolism , Mice , Mice, Transgenic , RNA, Messenger/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Rosuvastatin Calcium , Sterols/metabolism , Triglycerides/blood , Triglycerides/genetics
13.
J Hypertens ; 20(10): 2029-37, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12359982

ABSTRACT

BACKGROUND: Vascular (interstitial) angiotensin (ANG) II production depends on circulating renin-angiotensin system (RAS) components. Mannose 6-phosphate (man-6-P) receptors and angiotensin II type 1 (AT(1)) receptors, via binding and internalization of (pro)renin and ANG II, respectively, could contribute to the transportation of these components across the endothelium. OBJECTIVE: To investigate the mechanism(s) contributing to transendothelial RAS component transport. METHODS: Human umbilical vein endothelial cells were cultured on transwell polycarbonate filters, and incubated with RAS components in the absence or presence of man-6-P, eprosartan or PD123319, to block man-6-P, AT(1) and angiotensin II type 2 (AT(2)) receptors, respectively. RESULTS: Apically applied (pro)renin and angiotensinogen slowly entered the basolateral compartment, in a similar manner as horseradish peroxidase, a molecule of comparable size that reaches the interstitium via diffusion only. Prorenin transport was unaffected by man-6-P. Apical ANG I and ANG II rapidly reached the basolateral fluid independent of AT(1) and AT(2) receptors. Basolateral ANG II during apical ANG I application was as high as apical ANG II, whereas during apical ANG II application it was lower. During basolateral ANG I application, ANG II generation occurred basolaterally only, in an angiotensin-converting enzyme (ACE)-dependent manner. CONCLUSIONS: Circulating (pro)renin, angiotensinogen, ANG I and ANG II enter the interstitium via diffusion, and interstitial ANG II generation is mediated, at least in part, by basolaterally located endothelial ACE.


Subject(s)
Endothelium, Vascular/metabolism , Renin-Angiotensin System/physiology , Angiotensin I/drug effects , Angiotensin I/metabolism , Angiotensin II/drug effects , Angiotensin II/metabolism , Angiotensinogen/metabolism , Angiotensinogen/pharmacology , Biological Transport/drug effects , Biological Transport/physiology , Endothelium, Vascular/cytology , Endothelium, Vascular/enzymology , Enzyme Precursors/metabolism , Enzyme Precursors/pharmacology , Horseradish Peroxidase/drug effects , Horseradish Peroxidase/metabolism , Humans , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/metabolism , Renin/drug effects , Renin/metabolism , Renin/pharmacology , Renin-Angiotensin System/drug effects , Serine Proteinase Inhibitors/metabolism , Serine Proteinase Inhibitors/pharmacology , Serum Albumin/metabolism , Serum Albumin/pharmacology , Umbilical Veins/cytology , Umbilical Veins/drug effects , Umbilical Veins/enzymology
14.
Biochem Pharmacol ; 63(9): 1755-61, 2002 May 01.
Article in English | MEDLINE | ID: mdl-12007578

ABSTRACT

Previous rodent studies suggested that the potent hypolipidemic agent 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-N-(trifluoromethyl-phenyl) carboxamide monohydrochloride (HOE 402) is an inducer of the LDL receptor (LDLR). Using wild-type and heterozygous and homozygous LDLR-deficient (LDLR+/0 and LDLR0/0) mice, fed a low or high cholesterol diet, we investigated whether HOE 402 specifically induces the LDLR and whether other pathways are affected. Upon treatment with 0.05% (w/w) HOE 402, the serum cholesterol levels of wild-type, LDLR+/0 and LDLR0/0 mice, were maximally reduced by 53, 56, and 73%, respectively (P<0.05), by reducing levels in very low density-lipoprotein (VLDL), intermediate density-lipoprotein (IDL), and low density-lipoprotein (LDL) cholesterol, whereas high density-lipoprotein (HDL) cholesterol levels were increased. The observations that HOE 402 exhibited no effect on in vivo clearance of 125I-labeled LDL in wild-type mice, and clearly reduced serum cholesterol levels in LDLR0/0 mice, indicate that the LDLR is not the main target for the compound. In wild-type mice, production of VLDL-TG, and cholesterol were reduced by more than 50% by HOE 402 (P<0.05), whereas VLDL apolipoprotein B (ApoB) secretion was unaffected, indicating that HOE 402 treatment changes the size, rather than the number of the secreted VLDL particles. The reduced VLDL production was accompanied by a 22% decreased hepatic cholesterol ester concentration (P<0.05). Additionally, HOE 402 treatment strongly reduced the aortic content of atherosclerotic lesions by 90 and 72% in LDLR+/0 and LDLR0/0 mice, respectively (P<0.01). In conclusion, HOE 402 is a potent cholesterol-lowering compound, which inhibits VLDL production, and consequently attenuates atherosclerosis development.


Subject(s)
Arteriosclerosis/prevention & control , Cholesterol/blood , Hypolipidemic Agents/therapeutic use , Imidazoles/therapeutic use , Lipoproteins, VLDL/metabolism , Pyrimidines/therapeutic use , Receptors, LDL/metabolism , Animals , Aorta/pathology , Disease Models, Animal , Lipids/blood , Mice , Mice, Knockout , Receptors, LDL/genetics
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