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Biomedical subjects

Lars B Nielsen

Publications and source records attributed to Lars B Nielsen.

At least 19 recordsLinked to original sources
PubMed2006

Placental triglyceride accumulation in maternal type 1 diabetes is associated with increased lipase gene expression.

Maternal diabetes can cause fetal macrosomia and increased risk of obesity, diabetes, and cardiovascular disease in adulthood of the offspring. Although increased transplacental lipid transport could be involved, the impact of maternal type 1 diabetes on molecular mechanisms for lipid transport in placenta is largely unknown. To examine whether maternal type 1 diabetes affects placental lipid metabolism, we measured lipids and mRNA expression of lipase-encoding genes in placentas from women with type 1 diabetes (n = 27) and a control group (n = 21). The placental triglyceride (TG) concentration and mRNA expression of endothelial lipase (EL) and hormone-sensitive lipase (HSL) were increased in placentas from women with diabetes. The differences were more pronounced in women with diabetes and suboptimal metabolic control than in women with diabetes and good metabolic control. Placental mRNA expression of lipoprotein lipase and lysosomal lipase were similar in women with diabetes and the control group. Immunohistochemistry showed EL protein in syncytiotrophoblasts facing the maternal blood and endothelial cells facing the fetal blood in placentas from both normal women and women with diabetes. These results suggest that maternal type 1 diabetes is associated with TG accumulation and increased EL and HSL gene expression in placenta and that optimal metabolic control reduces these effects.

Case-Control Studies↗
PubMed2006

Apolipoprotein M--a novel player in high-density lipoprotein metabolism and atherosclerosis.

PURPOSE OF REVIEW: Apolipoprotein M is a recently described apolipoprotein predominantly associated with high-density lipoprotein, but also found in chylomicrons, very low-density lipoproteins, and low-density lipoprotein. The purpose is to review recent information on the unusual structural properties of apolipoprotein M and its possible role in formation of pre-beta high-density lipoprotein and reverse cholesterol metabolism. RECENT FINDINGS: Apolipoprotein M is a lipocalin having a coffee filter-like structure with a hydrophobic ligand-binding pocket. Mature apolipoprotein M retains its signal peptide, which serves as a hydrophobic anchor. In mice, silencing of expression in the liver with siRNA led to disappearance of pre-beta high-density lipoprotein and appearance of unusually large high-density lipoproteins. This suggests that apolipoprotein M is important for the formation of pre-beta high-density lipoprotein and reverse cholesterol transport. In accordance with this idea, hepatic overexpression of apolipoprotein M with an adenovirus in low-density lipoprotein-receptor deficient mice led to an approximately 70% reduction of atherosclerosis. In addition to the liver, apolipoprotein M is also expressed in the kidney. Kidney-derived apolipoprotein M binds to megalin, a member of the low-density lipoprotein-receptor family, which interacts with many lipocalins in renal tubuli. Apolipoprotein M is excreted in the urine of mice with a kidney-specific megalin deficiency but not in the urine of normal mice, suggesting megalin-mediated uptake of apolipoprotein M in the tubular epithelium of normal mice. SUMMARY: Apolipoprotein M is a novel apolipoprotein with unusual structural features that appears to play important roles in high-density lipoprotein metabolism and prevention of atherosclerosis.

Animals↗
PubMed2005

Uremia-specific effects in the arterial media during development of uremic atherosclerosis in apolipoprotein E-deficient mice.

OBJECTIVE: Uremia accelerates formation of atherosclerosis-like lesions in apolipoprotein E-deficient (apoE(-/-)) mice. In this study, we compared gene expression patterns in classical and uremic atherosclerosis. METHODS AND RESULTS: High-density oligonucleotide microarray analyses were performed with aortic RNA from 5/6 nephrectomized (NX) and sham-operated mice. After 12 weeks, NX apoE(-/-) mice had more atherosclerosis and 24 genes were differentially expressed as compared with sham apoE(-/-) mice. Nine genes expressed in muscle cells displayed reduced expression (3.3- to 142-fold, P<0.05), whereas osteopontin gene expression was increased 8.7-fold (P<0.05) in NX mice. Studies of NX wild-type mice suggested that the changes in NX apoE(-/-) mice were dependent on hypercholesterolemia. Nevertheless, lesioned versus nonlesioned areas of aortas from nonuremic apoE(-/-) mice with classical atherosclerosis displayed less pronounced reductions in expression of the muscle cell related genes than seen in NX apoE(-/-) mice even though the osteopontin gene expression was increased approximately 15-fold. Electron microscopy showed more vacuolized and necrotic smooth muscle cells within the media underneath both nonlesioned and lesioned intima in NX than in sham apoE(-/-) mice. CONCLUSIONS: The results suggest that uremic vasculopathy in apoE(-/-) mice, in addition to intimal atherosclerosis, is characterized by a uremia-specific medial smooth muscle cell degeneration, which appears to be accentuated by hypercholesterolemia.

Actins↗
PubMed2005

Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy.

Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg.kg(-1).day(-1)) to investigate a possible role of the renin-angiotensin system in regulation of natriuretic peptide and NPR gene expression. The ascending aorta was banded in 84 rats during Hypnorm/Dormicum-isoflurane anesthesia; after 4 wk the rats were randomized to treatment with losartan or placebo. The left ventricle of the heart was removed 1, 2, or 4 wk later. Aortic banding increased left ventricular expression of NPR-A and NPR-C mRNA by 110% (P < 0.001) and 520% (P < 0.01), respectively, after 8 wk; as expected, it also increased the expression of ANP and BNP mRNAs. Losartan induced a slight reduction of left ventricular weight but did not affect the expression of mRNAs for the natriuretic peptides or their receptors. Although increased gene expression does not necessarily convey a higher concentration of the protein, the data suggest that pressure overload is accompanied by upregulation of not only ANP and BNP but also their receptors NPR-A and NPR-C in the left ventricle.

Animals↗
PubMed2005

Increased plasma pro-B-type natriuretic peptide in infants of women with type 1 diabetes.

BACKGROUND: Up to 40% of newborn infants of women with type 1 diabetes have echocardiographic signs of cardiomyopathy. Increased plasma concentrations of B-type natriuretic peptide (BNP) and its precursor (proBNP) are markers of cardiac failure and hypoxia in adults. In this study, we investigated whether plasma concentrations of proBNP and/or BNP are increased in infants of women with type 1 diabetes. METHODS: Plasma BNP and proBNP were measured with RIAs. The proBNP assay measures both intact proBNP and NH(2)-terminal fragments derived from this precursor, whereas the BNP assay measures only BNP-32 and not proBNP. RESULTS: Infants of women with diabetes and hemoglobin A(1c) (Hb A(1c)) > or =6.2% before delivery had a higher median plasma proBNP concentration (31 pmol/L; interquartile range, 21-47 pmol/L; n = 16) than infants of healthy women [16 (9-32) pmol/L; n = 21; P = 0.01]. Infants of women with diabetes and Hb A(1c) <6.2% (n = 15) had intermediate values. The plasma BNP and proBNP concentrations were closely associated (r(2) = 0.80; P < 0.0001); within the group of infants of women with diabetes and Hb A(1c) > or =6.2%, both correlated with the degree of fetal stress during labor. CONCLUSIONS: Maternal diabetes and suboptimal metabolic control may affect the fetal heart and predominantly stimulate proBNP secretion in conjunction with perinatal stress.

Case-Control Studies↗
PubMed2005

Endothelial and lipoprotein lipases in human and mouse placenta.

Placenta expresses various lipase activities. However, a detailed characterization of the involved genes and proteins is lacking. In this study, we compared the expression of endothelial lipase (EL) and LPL in human term placenta. When placental protein extracts were separated by heparin-Sepharose affinity chromatography, the EL protein eluted as a single peak without detectable phospholipid or triglyceride (TG) lipase activity. The major portion of LPL protein eluted slightly after EL. This peak also had no lipase activity and most likely contained monomeric LPL. Fractions eluting at a higher NaCl concentration contained small amounts of LPL protein (most likely dimeric LPL) and had substantial TG lipase activity. In situ hybridization studies showed EL mRNA expression in syncytiotrophoblasts and endothelial cells and LPL mRNA in syncytiotrophoblasts. In contrast, immunohistochemistry showed EL and LPL protein associated with both cell types. In mouse placentas, lack of LPL expression resulted in increased EL mRNA expression. These results suggest that the cellular expression of EL and LPL in human placenta is different. Nevertheless, the two lipases might have overlapping functions in the mouse placenta. Our data also suggest that the major portions of both proteins are stored in an inactive form in human term placenta.

Animals↗
PubMed2004

Expression of the endothelial lipase gene in murine embryos and reproductive organs.

Endothelial lipase (EL) is a recently discovered member of the triglyceride-lipase family that is involved in plasma HDL metabolism. In this study, we investigated the putative role of EL in mouse reproduction by studying EL gene expression in mouse embryos and adult reproductive organs. PCR analysis revealed that EL mRNA is expressed in mouse embryos on embryonic day 8.5 (E8.5) to E11.5, but not later in development. In situ hybridization studies on E10.5 whole embryos and embryonic sections showed expression of EL mRNA in multiple tissues, although of varying intensity. High expression was found in the neuroepithelium of the brain and the neural tube, the mesenchymal cells between organs, the optic lens and cup, and the otocyst. In adult mice, EL mRNA expression was high in ovaries from pregnant mice but low in ovaries from nonpregnant mice. EL mRNA was also highly expressed in placenta and testes. In situ hybridization studies demonstrated intense EL mRNA staining of lutein cells in corpora lutei in ovaries, of spermatocytes in the late pachytene and diplotene stages in testes, and of principal cells in epididymis. These results suggest that EL, in addition to its effects on plasma lipoprotein metabolism, plays a role in murine reproduction.

Animals↗
PubMed2004

Human placenta secretes apolipoprotein B-100-containing lipoproteins.

Supply of lipids from the mother is essential for fetal growth and development. In mice, disruption of yolk sac cell secretion of apolipoprotein (apo) B-containing lipoproteins results in embryonic lethality. In humans, the yolk sac is vestigial. Nutritional functions are instead established very early during pregnancy in the placenta. To examine whether the human placenta produces lipoproteins, we examined apoB and microsomal triglyceride transfer protein (MTP) mRNA expression in placental biopsies. ApoB and MTP are mandatory for assembly and secretion of apoB-containing lipoproteins. Both genes were expressed in placenta and microsomal extracts from human placenta contained triglyceride transfer activity, indicating expression of bioactive MTP. To detect lipoprotein secretion, biopsies from term placentas were placed in medium with [(35)S]methionine and [(35)S]cysteine for 3-24 h. Upon sucrose gradient ultracentrifugation of the labeled medium, fractions were analyzed by apoB-immunoprecipitation. (35)S-labeled apoB-100 was recovered in d approximately 1.02-1.04 g/ml particles (i.e. similar to the density of plasma low density lipoproteins). Electron microscopy of negatively stained lipoproteins secreted from placental tissue showed spherical particles with a diameter of 47 +/- 10 nm. These results demonstrate that human placenta expresses both apoB and MTP and consequently synthesize and secrete apoB-100-containing lipoproteins. Placental lipoprotein formation constitutes a novel pathway of lipid transfer from the mother to the developing fetus.

Animals↗
PubMed2004

Photonic crystal fiber based evanescent-wave sensor for detection of biomolecules in aqueous solutions.

We demonstrate highly efficient evanescent-wave detection of fluorophore-labeled biomolecules in aqueous solutions positioned in the air holes of the microstructured part of a photonic crystal fiber. The air-suspended silica structures located between three neighboring air holes in the cladding crystal guide light with a large fraction of the optical field penetrating into the sample even at wavelengths in the visible range. An effective interaction length of several centimeters is obtained when a sample volume of less than 1 microL is used.

Biocompatible Materials↗
PubMed2004

The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease.

BACKGROUND: The microsomal triglyceride transfer protein (MTP) transfers lipids into apolipoprotein B-containing lipoproteins for secretion from liver, intestine, and heart. The T-variant of a functional polymorphism in the MTP promoter, MTP-493G/T, has been associated with reduced low-density lipoprotein cholesterol concentrations. We hypothesize that this polymorphism impacts on coronary heart disease (CHD) risk. METHODS AND RESULTS: The effect of the polymorphism was therefore tested in the West of Scotland Coronary Prevention Study biobank (580 cases and 1160 controls). MTP-493T carrier status was associated with significantly increased risk of CHD despite a small reduction in total cholesterol. Compared with the genotypic group with the lowest event rate (MTP-493GG, pravastatin treatment), the respective odds ratios (95% confidence interval) in the placebo group for CHD events were: GG, 1.23 (0.92 to 1.63); GT, 1.53 (1.12 to 2.08); and TT, 2.78 (1.53 to 5.05), suggestive of a gene-dose effect. The excess risk for CHD of the MTP-493T-variant was eliminated by pravastatin treatment. The Uppsala Longitudinal Study of Adult Men (ULSAM), which is a 20-year follow-up study of CHD, was used as an independent confirmatory database. These unexpected findings prompted the investigation of non-plasma lipid factors that could associate the MTP gene with CHD risk. In a limited number of subjects (n=18), heart muscle biopsies showed a MTP-493T genotype-specific depression of MTP mRNA expression. CONCLUSIONS: The MTP-493T variant confers an increased risk of CHD that is unrelated to plasma lipids and lipoproteins, but eliminated by pravastatin treatment. A direct effect of the MTP polymorphism on myocardial lipid metabolism and vulnerability upon ischemic damage cannot be excluded.

Abetalipoproteinemia↗
PubMed2004

Increased expression of adhesion molecules in uremic atherosclerosis in apolipoprotein-E-deficient mice.

Chronic renal failure markedly accelerates atherosclerosis in apolipoprotein-E-deficient mice, but the mechanism is unknown. The recruitment of inflammatory cells in the arterial wall by vascular adhesion molecules plays a key role in the formation of classical atherosclerosis. This study examines whether the expression of vascular adhesion molecules is increased in uremic atherosclerosis. Uremia was induced by 5/6 nephrectomy; control mice were sham-operated. After 2 wk of uremia, no lesion formation could be demonstrated in uremic or control mice. After 12 wk, aortas from uremic mice had a 9.8-fold increase of the aortic plaque area fraction compared with control mice (P < 0.0001). The aortic expression of intercellular adhesion molecule-1 (ICAM-1) mRNA in uremic mice was 215 +/- 31% (P < 0.05) and 243 +/- 55% (P < 0.05) of that in controls after 2 and 12 wk, respectively (n = 9 x 4). In contrast, aortic expression of vascular cell adhesion molecule-1 (VCAM-1) mRNA in uremic mice was unchanged after 2 wk but increased to 237 +/- 40% (P < 0.01) of that in control mice after 12 wk. On immunohistochemistry of aortas from uremic mice, ICAM-1 was predominantly present in endothelial cells both in nonlesioned and lesioned aortas, whereas VCAM-1 was predominantly present in the medial smooth muscle cell layer in lesioned aortas. The plasma concentration of soluble ICAM-1 (sICAM-1) (but not of sVCAM-1) was slightly elevated after 2 wk of uremia. In contrast, both sICAM-1 and sVCAM-1 plasma concentrations were markedly higher in uremic than control mice after 12 wk. These results suggest that uremic atherosclerosis is preceded by an upregulation of ICAM-1 expression in arterial endothelium and that formation of early uremic lesions is accompanied by upregulation of VCAM-1 expression in the medial smooth muscle cell layer.

Animals↗
PubMed2003

New tools for quantifying and visualizing adoptively transferred cells in recipient mice.

Adoptive transfer of donor cells in mice is widely used in research on the function and metabolism of lymphocytes. We have evaluated new approaches for quantifying and visualizing adopted cells in recipient mouse tissue. We injected spleen cells from male beta-galactosidase (LacZ) transgenic mice into female wild type mice and assessed the robustness of real-time PCR for quantifying the accumulation of the donor cells in blood and tissues of the recipient mice. The clearance of donor cells from the blood and their recruitment in lung, spleen, liver, and kidney was almost identical when obtained with amplification of the donor cell-specific LacZ or sex-determining region on the Y-chromosome (SRY) gene. We found, however, a marked difference in the PCR amplification efficiency of genomic DNA of different tissues, which should be taken into account when comparing recruitment of donor cells in different tissues. To visualize adoptively transferred cells, we used either spleen cells from transgenic mice, which express a Green Fluorescent Protein (GFP) transgene or spleen cells that had been fluorescence labeled ex vivo with CellTracker Orange. Whereas ex vivo and in vivo labeled donor cells could easily be detected in recipient mouse tissue by laser scanning confocal microscopy, only CellTracker Orange-labeled cells could be detected by conventional fluorescence microscopy due to autofluorescence in the examined tissues. Importantly, CellTracker Orange labeling did not appear to affect the blood clearance or the tissue accumulation of the donor cells. Together, the results demonstrate the usefulness of new protocols for quantifying and visualizing adoptively transferred cells by genetic tracing or fluorescence labeling.

Adoptive Transfer↗
PubMed2003

Aortic recruitment of blood lymphocytes is most pronounced in early stages of lesion formation in apolipoprotein-E-deficient mice.

Lymphocyte accumulation in the arterial intima affects development of atherosclerotic lesions. We studied the kinetics of lymphocyte accumulation in the arterial wall by injecting lymphocytes from male LacZ transgenic mice into female apolipoprotein-E-deficient mice. Recipient mouse aortas were removed and separated into lesioned and non-lesioned parts 2, 24, 48, or 72 h later. The accumulation of donor lymphocytes was quantified with real-time PCR of donor lymphocyte-specific genes. The accumulation of lymphocytes in the lesioned parts of aorta decreased with increasing lesion severity (r=-0.74, P=0.0005, n=18). Moreover, the accumulation of lymphocytes in the lesioned part of aorta was larger (392+/-108%, P=0.016) compared with the accumulation in the non-lesioned part in mice with mild atherosclerosis, whereas it was smaller (58+/-19%, P<0.01) compared with the accumulation in the non-lesioned part in mice with severe atherosclerosis. The results suggest that aortic recruitment of blood lymphocytes is most pronounced in early stages of lesion formation.

Animals↗
PubMed2003

Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice.

Cardiovascular mortality is 10 to 20 times increased in patients with chronic renal failure (CRF). Risk factors for atherosclerosis are abundant in patients with CRF. However, the pathogenesis of cardiovascular disease in CRF remains to be elucidated. The effect of CRF on the development of atherosclerosis in apolipoprotein E-deficient male mice was examined. Seven-week-old mice underwent 5/6 nephrectomy (CRF, n = 28), unilateral nephrectomy (UNX, n = 24), or no surgery (n = 23). Twenty-two weeks later, CRF mice showed increased aortic plaque area fraction (0.266 +/- 0.033 versus 0.045 +/- 0.006; P < 0.001), aortic cholesterol content (535 +/- 62 versus 100 +/- 9 nmol/cm(2) intimal surface area; P < 0.001), and aortic root plaque area (205,296 +/- 22,098 versus 143,662 +/- 13,302 micro m(2); P < 0.05) as compared with no-surgery mice; UNX mice showed intermediate values. The plaques from uremic mice contained CD11b-positive macrophages and showed strong staining for nitrotyrosine. Systolic BP and plasma homocysteine concentrations were similar in uremic and nonuremic mice. Plasma urea and cholesterol concentrations were elevated 2.6-fold (P < 0.001) and 1.5-fold (P < 0.001) in CRF compared with no-surgery mice. Both variables correlated with aortic plaque area fraction (r(2) = 0.5, P < 0.001 and r(2) = 0.3, P < 0.001, respectively) and with each other (r(2) = 0.5, P < 0.001). On multiple linear regression analysis, only plasma urea was a significant predictor of aortic plaque area fraction. In conclusion, the present findings suggest that uremia markedly accelerates atherogenesis in apolipoprotein E-deficient mice. This effect could not be fully explained by changes in BP, plasma homocysteine levels, or total plasma cholesterol concentrations. Thus, the CRF apolipoprotein E-deficient mouse is a new model for studying the pathogenesis of accelerated atherosclerosis in uremia.

Animals↗