48 results on '"Christoffersen, Christina"'
Search Results
2. Apolipoprotein M and its impact on endothelial dysfunction and inflammation in the cardiovascular system.
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Yao Mattisson, Ingrid and Christoffersen, Christina
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CARDIOVASCULAR system , *ENDOTHELIUM diseases , *HIGH density lipoproteins , *CARDIOVASCULAR diseases , *ENDOTHELIAL cells - Abstract
Apolipoprotein M (apoM) is a member of the lipocalin superfamily and is predominantly associated with high-density lipoprotein (HDL). It was found that apoM is the chaperon to the bioactive sphingolipid, sphingosine-1-phosphate (S1P). Several studies have since contributed to expand the knowledge on apoM, S1P, and the apoM/S1P-complex in cardiovascular diseases. For instance, the HDL-bound apoM/S1P complex serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. Evidence indicates, however, that the apoM/S1P complex may has both protective and harmful effects on the cardiovascular system, which suggests the need for more research to understand the interplay between these molecules. This review aims to shed light on the most recent findings on apoM/S1P-signaling and its impact on endothelial dysfunction, inflammation, and cardiovascular diseases. Finally, it will be discussed whether drugs that target apoM and/or S1P-signaling may be beneficial to patients with cardiovascular and inflammatory diseases. [Display omitted] • An imbalanced apoM/S1P-axis can interfere with triglyceride turnover and endothelial functions. • S1P-analogues may introduce a risk of disrupting the natural apoM/S1P axis and thereby the endothelial barrier homeostasis. • ApoM and S1P levels may predict the outcome of sepsis severity and SARS-CoV2. • ApoM and S1P may serve as a target in restoring endothelial dysfunction. [ABSTRACT FROM AUTHOR]
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- 2021
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3. The cellular composition of chronic subdural hematoma.
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Jensen, Thorbjørn Søren Rønn, Olsen, Markus Harboe, Christoffersen, Christina, Binderup, Tina, and Fugleholm, Kåre
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SUBDURAL hematoma , *LEUCOCYTES , *CELL size , *CELL analysis , *RETICULOCYTES , *MEAN platelet volume - Abstract
Introduction: The pathophysiology of chronic subdural hematoma (CSDH) remains to be fully understood. Basic knowledge of the composition and features of cells in the CSDH fluid may contribute to the understanding of the seemingly complex processes involved in CSDH formation and recurrence. This study is the first to examine the composition of cells and of cellular features in both systemic blood and subdural fluid from CSDH patients. We hypothesized that the cellular composition and features in the hematoma fluid may be; 1) different from that in the systemic blood; 2) different between patients with and without recurrence; 3) and different between the first and second operation in patients with recurrent CSDH. Methods: Systemic blood and subdural hematoma fluid were collected from CSDH patients with and without recurrent CSDH at the time of primary and secondary surgery. Analyses of cells and cellular features included total number of white blood cells, erythroblasts, reticulocytes, platelets, neutrophilocytes, lymphocytes, monocytes, eosinophils, basophils, reticulocytes, immature granulocytes, mean corpuscular cell volume (MCV), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin and hematocrit. Results: Of the 85 included patients, 20 patients were operated for a recurrent CSDH within 90 days follow-up. All cells found in the systemic blood were present in the CSDH fluid, but the composition was different (p < 0.0001). MCV was higher in the hematoma fluid from the primary operation of patients later developing a recurrent CSDH compared to patients not developing recurrence (p = 0.009). Also, the percentage distribution of inflammatory cells in hematoma fluid from patients with recurrent CSDH was different between the first and second operation (p = 0.0017). Conclusion: This study is the first to investigate the cellular composition of CSDH fluid. Compared to systemic blood and to a reference distribution, an increased number of immune cells were present in the hematoma fluid, supporting an inflammatory component of the CSDH pathophysiology. MCV was higher in the subdural fluid at time of the first operation of CSDH patients later developing recurrence. Clinical trial registration: The study was approved by the Scientific Ethical Committee of the Capital Region of Denmark (Journal no. H-20051073. [ABSTRACT FROM AUTHOR]
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- 2024
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4. ApoB and apoM – New aspects of lipoprotein biology in uremia-induced atherosclerosis.
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Christoffersen, Christina, Bartels, Emil D., Aarup, Annemarie, Nielsen, Lars B., and Pedersen, Tanja X.
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KIDNEY disease risk factors , *CARDIOVASCULAR diseases risk factors , *ATHEROSCLEROSIS , *APOLIPOPROTEIN B , *UREMIA - Abstract
Chronic kidney disease affects as much as 13% of the population, and is associated with a markedly increased risk of developing cardiovascular disease. One of the underlying reasons is accelerated development of atherosclerosis. This can be ascribed both to increased occurrence of traditional cardiovascular risk factors, and to risk factors that may be unique to patients with chronic kidney disease. The latter is reflected in the observation that the current treatment modalities, mainly directed against traditional risk factors, are insufficient to prevent cardiovascular disease in the patient with chronic kidney disease. This review discusses mechanisms accelerating uremic atherosclerosis with a specific focus on the putative roles of apolipoprotein(apo)s B and M that may be particularly important in patients with chronic kidney disease. [ABSTRACT FROM AUTHOR]
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- 2017
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5. A Novel Perspective on the ApoM-S1P Axis, Highlighting the Metabolism of ApoM and Its Role in Liver Fibrosis and Neuroinflammation.
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Hajny, Stefan and Christoffersen, Christina
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LIVER cells , *LIVER microsomes , *APOLIPOPROTEINS , *BLOOD lipoproteins , *SPHINGOSINE-1-phosphate , *HEPATIC fibrosis - Abstract
Hepatocytes, renal proximal tubule cells as well as the highly specialized endotheliumof the blood brain barrier (BBB) express and secrete apolipoprotein M (apoM). ApoM is a typical lipocalin containing a hydrophobic binding pocket predominantly carrying Sphingosine-1-Phosphate (S1P). The small signaling molecule S1P is associated with several physiological as well as pathological pathways whereas the role of apoM is less explored. Hepatic apoM acts as a chaperone to transport S1P through the circulation and kidney derived apoM seems to play a role in S1P recovery to prevent urinal loss. Finally, polarized endothelial cells constituting the lining of the BBB express apoM and secrete the protein to the brain as well as to the blood compartment. The review will provide novel insights on apoM and S1P, and its role in hepatic fibrosis, neuroinflammation and BBB integrity. [ABSTRACT FROM AUTHOR]
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- 2017
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6. Sphingosine-1-phosphate reduces ischaemia-- reperfusion injury by phosphorylating the gap junction protein Connexin43.
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Morel, Sandrine, Christoffersen, Christina, Axelsen, Lene N., Montecucco, Fabrizio, Rochemont, Viviane, Frias, Miguel A., Mach, Francois, James, Richard W., Naus, Christian C., Chanson, Marc, Lampe, Paul D., Nielsen, Morten S., Nielsen, Lars B., and Kwak, Brenda R.
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SPHINGOSINE-1-phosphate , *ISCHEMIA , *REPERFUSION injury , *PHOSPHORYLATION , *GAP junctions (Cell biology) , *CONNEXIN 43 , *LIPOPROTEINS , *HEART cells - Abstract
Aim Increasing evidence points to lipoprotein composition rather than reverse cholesteroltransport in the cardioprotective properties of high-density lipoproteins (HDLs). HDL binding to receptors at the surface of cardiomyocytes activates signalling pathways promoting survival, but downstream targets are largely unknown. Here, we investigate the pathways by which the sphingosine-1-phosphate (S1P) constituent of HDL limits cell death induced by cardiac ischaemiareperfusion (I/R). Methods and results Apolipoprotein M (ApoM) transgenic (Apom-Tg) mice, in which plasma S1P is increased by 296%, and wild-type (WT) mice were subjected to in vivo I/R. Infarct size, neutrophil infiltration into the infarcted area, and serum Troponin I were less pronounced in Apom-Tg mice. In vitro experiments suggest that this cardioprotection depends on direct effects of S1P on cardiomyocytes, whereas leucocyte recruitment seems only indirectly affected. Importantly, short-term S1P treatment at the onset of reperfusion was sufficient to reduce I/R injury in isolated perfused hearts. Mechanistic in vitro and ex vivo studies revealed that 5 min of S1P treatment induced phosphorylation of the gap junction protein Connexin43 (Cx43) on Serine368 (S368), which was mediated by S1P2 and S1P3, but not by S1P1, receptors in cardiomyocytes. Finally, S1P-induced reduction of infarct size after ex vivo I/R was lost in hearts of mice with a truncated C-terminus of Cx43 (Cx43K258/KO) or in which the S368 is mutated to a non-phosphorylatable alanine (Cx43S368A/S368A). Conclusion Our study reveals an important molecular pathway by which modulating the apoM/S1P axis has a therapeutic potential in the fight against I/R injury in the heart. [ABSTRACT FROM AUTHOR]
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- 2016
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7. Apolipoprotein M promotes mobilization of cellular cholesterol in vivo.
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Elsøe, Sara, Christoffersen, Christina, Luchoomun, Jayraz, Turner, Scott, and Nielsen, Lars Bo
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APOLIPOPROTEINS , *CHOLESTEROL , *HIGH-density lipoprotein receptors , *ATHEROSCLEROSIS , *MACROPHAGES , *LABORATORY mice - Abstract
Objective: The HDL associated apolipoprotein M (apoM) protects against experimental atherosclerosis but the mechanism is unknown. ApoM increases preβ-HDL formation. We explored whether plasma apoM affects mobilization of cholesterol from peripheral cells in mice. Methods and results: ApoM-enriched HDL from apoM-transgenic mice increased the in vitro efflux of 3H-cholesterol from macrophages by 24±3% (p<0.05) as compared with HDL from wild type (WT) mice, thus confirming previous findings. However, apoM-free HDL was not poorer than that of WT HDL to mobilize 3H-cholesterol. 3H-cholesterol-labeled foam cells were implanted in the peritoneal cavity of apoM−/−, WT and apoM-transgenic mice to assess the mobilization of cholesterol from foam cells in vivo and subsequent excretion into feces. The results showed a statistically non-significant trend towards increased mobilization of cellular cholesterol to plasma with increasing plasma apoM. However, the apoM-genotype did not affect the excretion of 3H-cholesterol in feces. Nevertheless, when apoM−/−, apoM-transgenic and WT mice received a constant intravenous infusion of 13C2-cholesterol/intralipid for 5h, the rate of enrichment of blood free cholesterol with free 13C2-cholesterol was significantly lower (consistent with an increase in flux of unlabeled free cholesterol into the plasma) in the apoM-transgenic (3.0±0.9‰/h) as compared to WT (5.7±0.9‰/h, p<0.05) and apoM−/− (6.5±0.6‰/h, p<0.01) mice. Conclusion: The present data indicate that the plasma apoM levels modulate the ability of plasma to mobilize cellular cholesterol, whereas apoM has no major effect on the excretion of cholesterol into feces. [ABSTRACT FROM AUTHOR]
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- 2013
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8. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M.
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Christoffersen, Christina, Obinata, Hideru, Kumaraswamy, Sunil B., Galvani, Sylvain, Ahnström, Josefin, Sevvana, Madhumati, Egerer-Sieber, Claudia, Muller, Yves A., Hla, Timothy, Nielsen, Lars B., and Dahlbäck, Björn
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VASCULAR endothelium , *SPHINGOSINE , *APOLIPOPROTEINS , *CELL migration , *HIGH density lipoproteins - Abstract
Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM+ HDL contained S1P, whereas ApoM- HDL did not. Moreover, HDL in Apom-/- mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM+ HDL induced S1P1 receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM- HDL did not. Importantly, lack of S1P in the HDL fraction of Apom-/- mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P1 receptor on endothelial cells, is a vasculoprotective constituent of HDL. [ABSTRACT FROM AUTHOR]
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- 2011
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9. ApoM: gene regulation and effects on HDL metabolism
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Nielsen, Lars B., Christoffersen, Christina, Ahnström, Josefin, and Dahlbäck, Björn
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LIPOPROTEINS , *BLOOD plasma , *GENETIC regulation , *METABOLISM - Abstract
The recently discovered apolipoprotein M (apoM) is a plasma protein of the lipocalin family associated with the lipoproteins (mainly high-density lipoproteins, or HDLs). Expression of the apoM gene in the liver is regulated by transcription factors that control key steps in hepatic lipid and glucose metabolism. Although the concentration of plasma apoM correlates with that of cholesterol, apoM was not identified as a risk factor for cardiovascular disease in two prospective studies. In genetically modified mice, however, changes in plasma apoM concentration caused quantitative and qualitative changes in HDLs, and overexpression of the apoM gene reduced atherosclerosis. In conclusion, it seems that apoM plays a part in lipoprotein metabolism; however, the biological impact of apoM in humans remains to be determined. [Copyright &y& Elsevier]
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- 2009
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10. The Signal Peptide Anchors Apolipoprotein M in Plasma Lipoproteins and Prevents Rapid Clearance of Apolipoprotein M from Plasma.
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Christoffersen, Christina, Ahnström, Josefin, Axier, Olof, Christensen, Erik Ilsø, Dahibäck, Bjärn, and Nielsen, Lars Bo
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APOLIPOPROTEINS , *LIPOPROTEINS , *PEPTIDES , *BLOOD lipoproteins , *BLOOD plasma - Abstract
Lipoproteins consist of lipids solubilized by apolipoproteins. The lipid-binding structural motifs of apolipoproteins include amphipathic α-helixes and β-sheets. Plasma apolipoprotein (apo) M lacks an external amphipathic motif but, nevertheless, is exclusively associated with lipoproteins (mainly high density lipoprotein). Uniquely, however, apoM is secreted to plasma without cleavage of its hydrophobic NH2-terminal signal peptide. To test whether the signal peptide serves as a lipoprotein anchor for apoM in plasma, we generated mice expressing a mutated apoMQ22A cDNA in the liver (apoMQ22A-Tg mice (transgenic mice)) and compared them with mice expressing wild-type human apoM (apoM-Tg mice). The substitution of the amino acid glutamine 22 with alanine in apoMQ22A results in secretion of human apoM without a signal peptide. The human apoM mRNA level in liver and the amount of human apoM protein secretion from hepatocytes were similar in apoM-Tg and apoMQ22A-Tg mice. Nevertheless, human apoM was not detectable in plasma of apoMQ22A-Tg mice, whereas it was easily measured in the apoM-Tg mice. To examine the plasma metabolism, recombinant apoM lacking the signal peptide was produced in Escherichia coli and injected into wild-type mice. The apoM without signal peptide did not associate with lipoproteins and was rapidly cleared in the kidney. Accordingly, ligation of the kidney arteries in apoMQ22A-Tg mice resulted in rapid accumulation of human apoM in plasma. The data suggest that hydrophohic signal peptide sequences, if preserved upon secretion, can anchor plasma proteins in lipoproteins. In the case of apoM, this mechanism prevents rapid loss by filtration in the kidney. [ABSTRACT FROM AUTHOR]
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- 2008
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11. Effect of Apolipoprotein M on High Density Lipoprotein Metabolism and Atherosclerosis in Low Density Lipoprotein Receptor Knock-out Mice.
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Christoffersen, Christina, Jauhiainen, Matti, Moser, Markus, Porse, Bo, Ehnholm, Christian, Boesl, Michael, Dahlbäck, Björn, and Nielsen, Lars Bo
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APOLIPOPROTEINS , *HIGH density lipoproteins , *LOW density lipoproteins , *ATHEROSCLEROSIS , *TRANSGENIC mice , *LABORATORY mice - Abstract
To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient (apoM-/-) mice. Plasma apoM was predominantly associated with 10-12-nm α-migrating HDL particles. Human apoM overexpression (11-fold) increased plasma cholesterol concentration by 13-22%, whereas apoM deficiency decreased it by 17-21%. The size and charge of apoA-I-containing HDL in plasma were not changed in apoM-Tg or apoM-/- mice. However, in plasma incubated at 37 °C, lecithin:cholesterol acyltransferase-dependent conversion of α- to pre-α-migrating HDL was delayed in apoM-Tg mice. Moreover, lecithin: cholesterol acyltransferase-independent generation of pre-β-migrating apoA-I-containing particles in plasma was increased in apoM-Tg mice (4.2 ± 1.1%, p = 0.06) and decreased in apoM-/- mice (0.5 ± 0.3%, p = 0.03) versus controls (1.8 ± 0.05%). In the setting of low density lipoprotein receptor deficiency, apoM-Tg mice with 2-fold increased plasma apoM concentrations developed smaller atherosclerotic lesions than controls. The effect of apoM on atherosclerosis may be facilitated by enzymatic modulation of plasma HDL particles, increased cholesterol efflux from foam cells, and an antioxidative effect of apoM-containing HDL. [ABSTRACT FROM AUTHOR]
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- 2008
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12. Transition Metal‐Oxide Nanomembranes Assembly by Direct Heteroepitaxial Growth.
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Li, Hang, Yun, Shinhee, Chikina, Alla, Rosendal, Victor, Tran, Thomas, Brand, Eric, Christoffersen, Christina H., Plumb, Nicholas C., Shi, Ming, Pryds, Nini, and Radovic, Milan
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The integration of complex oxides with a wide range of functionalities on conventional semiconductor platforms is highly demanded for functional applications. Despite continuous efforts to integrate complex oxides on Si, it is still challenging to harvest epitaxial layers using standard deposition processes. Here, a novel method is demonstrated to create high‐quality complex heterostructures on Si integrated with SrTiO3 membranes as a universal platform. The STO membrane successfully bridges a broad spectrum of complex heterostructures such as SrNbO3, SrVO3, TiO2, and dichalcogenide 2D superconducting FeSe toward semiconducting wafers (Si). Through electronic structures measured by angle‐resolved photoemission spectroscopy, the high quality and functionality of the heterostructures are verified. This study demonstrated a new pathway toward realizing electronic devices with multifunctional physical properties incorporated into Si. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Plasma activin A rises with declining kidney function and is independently associated with mortality in patients with chronic kidney disease.
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Nordholm, Anders, Sørensen, Ida M H, Bjergfelt, Sasha S, Fuchs, Andreas, Kofoed, Klaus F, Landler, Nino E, Biering-Sørensen, Tor, Carlson, Nicholas, Feldt-Rasmussen, Bo, Christoffersen, Christina, and Bro, Susanne
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RENAL osteodystrophy , *CHRONIC kidney failure , *KIDNEY physiology , *CHRONICALLY ill , *MAJOR adverse cardiovascular events - Abstract
Background Plasma (p-)activin A is elevated in chronic kidney disease–mineral and bone disorder (CKD-MBD). Activin A inhibition ameliorates CKD-MBD complications (vascular calcification and bone disease) in rodent CKD models. We examined whether p-activin A was associated with major adverse cardiovascular events (MACE), all-cause mortality and CKD-MBD complications in CKD patients. Methods The study included 916 participants (741 patients and 175 controls) from the prospective Copenhagen CKD cohort. Comparisons of p-activin A with estimated glomerular filtration rate (eGFR), coronary and thoracic aorta Agatston scores, and bone mineral density (BMD) were evaluated by univariable linear regression using Spearman's rank correlation, analysis of covariance and ordinal logistic regression with adjustments. Association of p-activin A with rates of MACE and all-cause mortality was evaluated by the Aalen–Johansen or Kaplan–Meier estimator, with subsequent multiple Cox regression analyses. Results P-activin A was increased by CKD stage 3 (124–225 pg/mL, P < .001) and correlated inversely with eGFR (r = −0.53, P < 0.01). P-activin A was associated with all-cause mortality [97 events, hazard ratio 1.55 (95% confidence interval 1.04; 2.32), P < 0.05] after adjusting for age, sex, diabetes mellitus (DM) and eGFR. Median follow-up was 4.36 (interquartile range 3.64–4.75) years. The association with MACE was not significant after eGFR adjustment. Agatston scores and BMD were not associated with p-activin A. Conclusion P-activin A increased with declining kidney function and was associated with all-cause mortality independently of age, sex, DM and eGFR. No association with MACE, vascular calcification or BMD was demonstrated. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH.
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Baandrup Kristiansen, Maria Nicoline, Veidal, Sanne Skovgård, Christoffersen, Christina, Feigh, Michael, Vrang, Niels, Roth, Jonathan David, Erickson, Mary, Adorini, Luciano, and Jelsing, Jacob
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PHARMACOLOGY , *PHARMACODYNAMICS , *ELEMENTAL diet , *HEPATOMEGALY , *DRUG efficacy , *LIVER analysis , *GALECTINS - Abstract
Background: Compounds in clinical development for nonalcoholic steatohepatitis (NASH) improve liver histopathology in diet-induced obese mouse models of biopsy-confirmed NASH. Since the biopsy section used for histopathological evaluation represents only < 1% of the whole mouse liver, we evaluated how well biopsy-based quantitative image analyses correlate to stereology-based whole-liver quantitative changes upon drug treatment.Methods: Male leptin-deficient Lepob/Lepob mice were fed the Amylin liver NASH (AMLN) diet for 16 weeks before stratification into treatment groups using a biopsy-based evaluation of type I collagen αI (col1a1) levels. Mice were treated for 8 weeks with either vehicle (PO, QD), liraglutide (0.4 mg/kg, SC, QD), elafibranor (30 mg/kg, PO, QD) or INT-767 (10 mg/kg, PO, QD). Terminal quantitative histological assessment of liver lipid (hematoxylin-eosin staining), inflammation (galectin-3 immunohistochemistry (IHC); gal-3), and fibrosis (col1a1 IHC) was performed on terminal liver biopsies and compared with stereologically sampled serial sections spanning the medial, left and right lateral lobe of the liver.Results: The distribution of liver lipid and fibrosis was markedly consistent across lobes, whereas inflammation showed some variability. While INT-767 and liraglutide significantly reduced total liver weight by 20 and 48%, respectively, elafibranor tended to exacerbate hepatomegaly in Lepob/Lepob-NASH mice. All three compounds markedly reduced biopsy-based relative liver lipid content. Elafibranor and INT-767 significantly reduced biopsy-based relative gal-3 levels (P < 0.001), whereas INT-767 and liraglutide tended to reduce relative col1a1 levels. When changes in liver weight was accounted for, both INT-767 and liraglutide significantly reduced biopsy-based total col1a1 content. Although minor differences in absolute and relative liver lipid, inflammation and fibrosis levels were observed across lobes, the interpretation of drug-induced effects were consistent with biopsy-based conclusions. Notably, the incorporation of changes in total liver mass revealed that liraglutide's efficacy reached statistical significances for all analyzed parameters.Conclusions: In conclusion, in-depth analyses of liver homogeneity demonstrated that drug-induced improvement in liver biopsy-assessed histopathology is representative for overall liver effects assessed using stereology. Importantly, these findings reveal how changes in whole-liver mass should be considered to provide a deeper understanding of apparent drug treatment efficacy in preclinical NASH studies. [ABSTRACT FROM AUTHOR]- Published
- 2019
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15. Apolipoprotein M-bound sphingosine-1-phosphate regulates blood-brain barrier paracellular permeability and transcytosis.
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Janiurek, Mette Mathiesen, Soylu-Kucharz, Rana, Christoffersen, Christina, Kucharz, Krzysztof, and Lauritzen, Martin
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BLOOD-brain barrier , *PERMEABILITY , *SPHINGOSINE-1-phosphate , *SMALL molecules , *ENDOTHELIAL cells , *OCCLUDINS , *CLAUDINS , *APOLIPOPROTEIN E4 - Abstract
The blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels, but how blood-borne signaling molecules influence permeability is incompletely understood. We here examined how the apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P) signaling pathway affects the BBB in different categories of cerebral microvessels using ApoM deficient mice (Apom-/-). We used two-photon microscopy to monitor BBB permeability of sodium fluorescein (376 Da), Alexa Fluor (643 Da), and fluorescent albumin (45 kDA). We show that BBB permeability to small molecules increases in Apom-/- mice. Vesicle-mediated transfer of albumin in arterioles increased 3 to 10-fold in Apom-/- mice, whereas transcytosis in capillaries and venules remained unchanged. The S1P receptor 1 agonist SEW2871 rapidly normalized paracellular BBB permeability in Apom-/- mice, and inhibited transcytosis in penetrating arterioles, but not in pial arterioles. Thus, apoM-bound S1P maintains low paracellular BBB permeability in all cerebral microvessels and low levels of vesicle-mediated transport in penetrating arterioles. [ABSTRACT FROM AUTHOR]
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- 2019
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16. Super-Resolution Ultrasound Imaging of Renal Vascular Alterations in Zucker Diabetic Fatty Rats during the Development of Diabetic Kidney Disease.
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Søgaard, Stinne Byrholdt, Andersen, Sofie Bech, Taghavi, Iman, Schou, Mikkel, Christoffersen, Christina, Jacobsen, Jens Christian Brings, Kjer, Hans Martin, Gundlach, Carsten, McDermott, Amy, Jensen, Jørgen Arendt, Nielsen, Michael Bachmann, and Sørensen, Charlotte Mehlin
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DIABETIC nephropathies , *HIGH resolution imaging , *ULTRASONIC imaging , *KIDNEY development , *LABORATORY rats - Abstract
Individuals with diabetes at risk of developing diabetic kidney disease (DKD) are challenging to identify using currently available clinical methods. Prognostic accuracy and initiation of treatment could be improved by a quantification of the renal microvascular rarefaction and the increased vascular tortuosity during the development of DKD. Super-resolution ultrasound (SRUS) imaging is an in vivo technique capable of visualizing blood vessels at sizes below 75 µm. This preclinical study aimed to investigate the alterations in renal blood vessels' density and tortuosity in a type 2 diabetes rat model, Zucker diabetic fatty (ZDF) rats, as a prediction of DKD. Lean age-matched Zucker rats were used as controls. A total of 36 rats were studied, subdivided into ages of 12, 22, and 40 weeks. Measured albuminuria indicated the early stage of DKD, and the SRUS was compared with the ex vivo micro-computed tomography (µCT) of the same kidneys. Assessed using the SRUS imaging, a significantly decreased cortical vascular density was detected in the ZDF rats from 22 weeks of age compared to the healthy controls, concomitant with a significantly increased albuminuria. Already by week 12, a trend towards a decreased cortical vascular density was found prior to the increased albuminuria. The quantified vascular density in µCT corresponded with the in vivo SRUS imaging, presenting a consistently lower vascular density in the ZDF rats. Regarding vessel tortuosity, an overall trend towards an increased tortuosity was present in the ZDF rats. SRUS shows promise for becoming an additional tool for monitoring and prognosing DKD. In the future, large-scale animal studies and human trials are needed for confirmation. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Subclinical atherosclerosis in patients with cyanotic congenital heart disease.
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Tarp, Julie Bjerre, Sørgaard, Mathias Holm, Christoffersen, Christina, Jensen, Annette Schophuus, Sillesen, Henrik, Celermajer, David, Eriksson, Peter, Estensen, Mette-Elise, Nagy, Edit, Holstein-Rathlou, Niels-Henrik, Engstrøm, Thomas, and Søndergaard, Lars
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CONGENITAL heart disease , *CONGENITAL disorders , *HEART diseases , *CAROTID artery , *ATHEROSCLEROSIS , *CYANOSIS - Abstract
Abstract Introduction Survival in patients with cyanotic congenital heart disease (CCHD) has improved dramatically. The result is an ageing population with risk of acquired heart disease. Previous small uncontrolled studies suggested that these patients are protected against the development of atherosclerosis. To test this hypothesis, we sought to determine the prevalence of subclinical atherosclerosis in a larger population of patients with CCHD. Method We compared the prevalence of subclinical atherosclerosis in adult CCHD patients from Denmark, Sweden, Norway and Australia, with that in age-, sex-, smoking status-, and body mass index matched controls. Coronary artery atherosclerosis was assessed on computed tomography with coronary artery calcification (CAC) score. Subclinical atherosclerosis was defined by CAC-score > 0. Carotid artery atherosclerosis was evaluated using ultrasound by measuring carotid plaque thickness (cPT-max) and carotid intima media thickness (CIMT). Lipid status was evaluated as an important atherosclerotic risk factor. Results Seventy-four patients with CCHD (57% women, median age 49.5 years) and 74 matched controls (57% women, median age 50.0 years) were included. There were no differences between the groups in: CAC-score > 0 (21% vs. 19%, respectively; p = 0.8), carotid plaques (19% vs. 9%, respectively; p = 0.1), cPT-max (2.3 mm vs. 2.8 mm, respectively; p = 0.1) or CIMT (0.61 mm vs. 0.61 mm, respectively; p = 0.98). And further no significant differences in lipoprotein concentrations measured by ultracentrifugation. Conclusion Young adults with CCHD have similar cardiovascular risk factor profiles and measures of subclinical atherosclerosis, compared with controls. Given their increasing life expectancies, athero-preventive strategies should be an important part of their clinical management. Highlights • CCHD patients do not have a decreased burden of atherosclerosis. • Patients with CCHD do not present with hypocholesterolemia. • CCHD patients have a high LDL/HDL-ratio and a high level of inflammatory markers. • CCHD patients may have an increased risk of atherosclerosis. [ABSTRACT FROM AUTHOR]
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- 2019
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18. Coronary and extra-coronary artery calcium scores as predictors of cardiovascular events and mortality in chronic kidney disease stages 1–5: a prospective cohort study.
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Sørensen, Ida M H, Bjergfelt, Sasha S, Hjortkjær, Henrik Ø, Kofoed, Klaus F, Lange, Theis, Feldt-Rasmussen, Bo, Christoffersen, Christina, and Bro, Susanne
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CORONARY artery calcification , *CHRONIC kidney failure , *CAROTID artery , *MULTIDETECTOR computed tomography , *ARTERIAL calcification - Abstract
Background Vascular calcification is a known risk factor for cardiovascular events and mortality in patients with chronic kidney disease (CKD). However, since there is a lack of studies examining several arterial regions at a time, we aimed to evaluate the risk of major adverse cardiovascular events (MACE) and all-cause mortality according to calcium scores in five major arterial sites. Methods This was a prospective study of 580 patients from the Copenhagen CKD Cohort. Multidetector computed tomography of the coronary and carotid arteries, the thoracic aorta, the abdominal aorta and the iliac arteries was used to determine vascular calcification at baseline. Calcium scores were divided into categories: 0, 1–100, 101–400 and >400. Results During the follow-up period of 4.1 years a total of 59 cardiovascular events and 64 all-cause deaths occurred. In Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, hypertension, diabetes mellitus, hypercholesterolemia and smoking, only the coronary and carotid arteries, and the thoracic aorta were independent predictors of the designated endpoints. When examining the potential of calcification in the five arterial sites for predicting MACE, the difference in C-statistic was also most pronounced in these three sites, at 0.21 [95% confidence interval (CI) 0.16%–0.26%, P < .001], 0.26 (95% CI 0.22%–0.3%, P < .001) and 0.20 (95% CI 0.16%–0.24%, P < .001), respectively. This trend also applied to all-cause mortality. Conclusions The overall results, including data on specificity, suggest that calcium scores of the coronary and carotid arteries have the most potential for identifying patients with CKD at high cardiovascular risk and for evaluating new therapies. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Effects of apolipoprotein M in uremic atherosclerosis.
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Madsen Svarrer, Eva Martha, Bosteen, Markus Høybye, Christoffersen, Christina, Nielsen, Lars Bo, Madsen, Marie, Pedersen, Tanja Xenia, Bisgaard, Line Stattau, and Martinussen, Torben
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APOLIPOPROTEINS , *KIDNEY diseases , *ATHEROSCLEROSIS , *NEPHRECTOMY , *INFLAMMATION , *THERAPEUTICS - Abstract
Background and aims Chronic kidney disease is characterized by uremia and causes premature death, partly due to accelerated atherosclerosis. Apolipoprotein (apo) M is a plasma carrier protein for the lipid sphingosine-1-phosphate (S1P). The Apom-S1P complex associates with HDL, and may contribute to its anti-atherosclerotic effects. The role of Apom/S1P in atherosclerosis is presently controversial and has not been explored in a uremic setting. We aimed to explore whether plasma concentrations of Apom/S1P are altered by uremia and whether Apom overexpression or deficiency affects classical and uremic atherosclerosis. Methods Mild to moderate uremia was induced by subtotal nephrectomy (NX) in 86–92 Apoe-deficient mice that were either Apom-wild type, Apom-deficient, or overexpressed Apom (∼10 fold). The effects of uremia on plasma Apom/S1P and atherosclerosis were evaluated and compared to non-nephrectomized controls. Results Uremia increased plasma Apom by ∼25%, but not S1P. Plasma S1P was elevated by ∼300% in mice overexpressing Apom, and decreased by ∼25% in Apom-deficient mice. Apom overexpression augmented aortic root atherosclerosis and plasma cholesterol. In contrast, aortic arch atherosclerosis was unaffected by the Apom genotype. There was no effect of Apom-deficiency or Apom overexpression on uremic atherosclerosis. Conclusions This study highlights the complexity of Apom/S1P in atherosclerosis and challenges the notion that the Apom/S1P complex is anti-atherogenic, at least in Apoe-deficient mice. [ABSTRACT FROM AUTHOR]
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- 2017
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20. Iodide as a potential therapeutic in atherosclerosis.
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Gamon, Luke F., Jokumsen, Kathrine V., Christoffersen, Christina, and Davies, Michael J.
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ATHEROSCLEROSIS , *IODIDES - Published
- 2023
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21. Association of apolipoprotein M and sphingosine-1-phosphate with brown adipose tissue after cold exposure in humans.
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Borup, Anna, Donkin, Ida, Boon, Mariëtte R., Frydland, Martin, Martinez-Tellez, Borja, Loft, Annika, Keller, Sune H., Kjaer, Andreas, Kjaergaard, Jesper, Hassager, Christian, Barrès, Romain, Rensen, Patrick C. N., and Christoffersen, Christina
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BROWN adipose tissue , *BATS , *SPHINGOSINE-1-phosphate , *METABOLIC regulation , *TISSUE metabolism , *LIPID metabolism , *POLYETHYLENE terephthalate - Abstract
The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism. ApoM deficiency in mice is associated with increased vascular permeability, brown adipose tissue (BAT) mass and activity, and protection against obesity. In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via 18F-FDG PET/CT after cold exposure in humans. Fixed (n = 15) vs personalized (n = 20) short-term cooling protocols decreased and increased apoM (− 8.4%, P = 0.032 vs 15.7%, P < 0.0005) and S1P (− 41.0%, P < 0.0005 vs 19.1%, P < 0.005) plasma levels, respectively. Long-term cooling (n = 44) did not affect plasma apoM or S1P levels. Plasma apoM and S1P did not correlate significantly to BAT volume and activity in the individual studies. However, short-term studies combined, showed that increased changes in plasma apoM correlated with BAT metabolic activity (β: 0.44, 95% CI [0.06–0.81], P = 0.024) after adjusting for study design but not BAT volume (β: 0.39, 95% CI [− 0.01–0.78], P = 0.054). In conclusion, plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity but not BAT volume in humans. This contrasts partly with observations in animals and highlights the need for further studies to understand the biological role of apoM/S1P complex in human adipose tissue and lipid metabolism. [ABSTRACT FROM AUTHOR]
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- 2022
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22. Super-Resolution Ultrasound Imaging Provides Quantification of the Renal Cortical and Medullary Vasculature in Obese Zucker Rats: A Pilot Study.
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Søgaard, Stinne Byrholdt, Andersen, Sofie Bech, Taghavi, Iman, Hoyos, Carlos Armando Villagómez, Christoffersen, Christina, Hansen, Kristoffer Lindskov, Jensen, Jørgen Arendt, Nielsen, Michael Bachmann, and Sørensen, Charlotte Mehlin
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HIGH resolution imaging , *LABORATORY rats , *ULTRASONIC imaging , *DISEASE risk factors , *OBESITY - Abstract
Obesity is a risk factor of chronic kidney disease (CKD), leading to alterations in the renal vascular structure. This study tested if renal vascular density and tortuosity was quantifiable in vivo in obese rats using microbubble-based super-resolution ultrasound imaging. The kidneys of two 11-week-old and two 20-week-old male obese Zucker rats were compared with age-matched male lean Zucker rats. The super-resolution ultrasound images were manually divided into inner medulla, outer medulla, and cortex, and each area was subdivided into arteries and veins. We quantified vascular density and tortuosity, number of detected microbubbles, and generated tracks. For comparison, we assessed glomerular filtration rate, albumin/creatinine ratio, and renal histology to evaluate CKD. The number of detected microbubbles and generated tracks varied between animals and significantly affected quantification of vessel density. In areas with a comparable number of tracks, density increased in the obese animals, concomitant with a decrease in glomerular filtration rate and an increase in albumin/creatinine ratio, but without any pathology in the histological staining. The results indicate that super-resolution ultrasound imaging can be used to quantify structural alterations in the renal vasculature. Techniques to generate more comparable number of microbubble tracks and confirmation of the findings in larger-scale studies are needed. [ABSTRACT FROM AUTHOR]
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- 2022
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23. The metabolic signature of cardiovascular disease and arterial calcification in patients with chronic kidney disease.
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Sørensen, Ida MH., Bisgaard, Line S., Bjergfelt, Sasha S., Ballegaard, Ellen LF., Biering-Sørensen, Tor, Landler, Nino E., Pedersen, Tanja X., Kofoed, Klaus F., Lange, Theis, Feldt-Rasmussen, Bo, Bro, Susanne, and Christoffersen, Christina
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ARTERIAL calcification , *CHRONIC kidney failure , *CARDIOVASCULAR diseases , *NUCLEAR magnetic resonance spectroscopy , *CORONARY artery calcification - Abstract
The relationship between chronic kidney disease (CKD) and cardiovascular events is well-established. Clinically recognised risk factors of cardiovascular disease cannot fully explain this association. The objective of the present cross-sectional study was to investigate associations between serum metabolites and prevalent cardiovascular disease, as well as subclinical cardiovascular disease measured as coronary artery calcium score (CACS) in patients with CKD. More than 200 preselected metabolites were quantified using nuclear magnetic resonance spectroscopy in 725 patients and 174 controls from the Copenhagen CKD Cohort. CACS was determined by computed tomography. Mean age of patients was 57.8 years, and 444 (61.3%) were men. Most of patients had hypercholesterolemia, and 133 (18.3%) had type 2 diabetes. Overall, 85 metabolites were significantly associated with prevalent cardiovascular disease in a model adjusted for eGFR, age, and sex, as well as Bonferroni correction for multiple testing (p < 0.001). After further adjusting for diabetes, BMI, smoking, and cholesterol-lowering medication, the significance was lost for all but six metabolites (concentration of ApoA-1, cholesterol in total HDL and HDL2, total lipids and phospholipids in large HDL particles, and the ratio of phospholipids to total lipids in smaller VLDL particles). Of the 85 metabolites associated with prevalent cardiovascular disease, 71 were also associated with CACS in a similar pattern. Yet, in the model adjusted for all seven cardiovascular risk factors, only serum glucose levels and the ratio of triglycerides to total lipids in larger LDL particles remained significant. In patients with CKD, associations with prevalent cardiovascular disease were mainly found for HDL-related metabolites, while CACS was associated with glucose levels and increased triglycerides to total lipids ratio in LDL particles. [Display omitted] • 85 metabolites were associated with cardiovascular disease (CVD). • 84 metabolites were associated with coronary artery calcium score (CACS). • After risk factor adjustment CVD was associated with HDL-related metabolites. • CACS was associated with glucose and triglycerides in larger LDL particles. • Metabolites other than LDL cholesterol may contribute to CVD in chronic kidney disease (CKD). [ABSTRACT FROM AUTHOR]
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- 2022
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24. Carotid plaque thickness is increased in chronic kidney disease and associated with carotid and coronary calcification.
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Bjergfelt, Sasha S., Sørensen, Ida M. H., Hjortkjær, Henrik Ø., Landler, Nino, Ballegaard, Ellen L. F., Biering-Sørensen, Tor, Kofoed, Klaus F., Lange, Theis, Feldt-Rasmussen, Bo, Sillesen, Henrik, Christoffersen, Christina, and Bro, Susanne
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CORONARY artery calcification , *CHRONIC kidney failure , *ATHEROSCLEROTIC plaque , *CARDIOVASCULAR diseases , *ARTERIAL calcification , *CAROTID artery - Abstract
Background: Chronic kidney disease accelerates both atherosclerosis and arterial calcification. The aim of the present study was to explore whether maximal carotid plaque thickness (cPTmax) was increased in patients with chronic kidney disease compared to controls and associated with cardiovascular disease and severity of calcification in the carotid and coronary arteries. Methods: The study group consisted of 200 patients with chronic kidney disease stage 3 from the Copenhagen Chronic Kidney Disease Cohort and 121 age- and sex-matched controls. cPTmax was assessed by ultrasound and arterial calcification by computed tomography scanning. Results: Carotid plaques were present in 58% of patients (n = 115) compared with 40% of controls (n = 48), p = 0.002. Among participants with plaques, cPTmax (median, interquartile range) was significantly higher in patients compared with controls (1.9 (1.4–2.3) versus 1.5 (1.2–1.8) mm), p = 0.001. Cardiovascular disease was present in 9% of patients without plaques (n = 85), 23% of patients with cPTmax 1.0–1.9 mm (n = 69) and 35% of patients with cPTmax >1.9 mm (n = 46), p = 0.001. Carotid and coronary calcium scores >400 were present in 0% and 4%, respectively, of patients with no carotid plaques, in 19% and 24% of patients with cPTmax 1.0–1.9 mm, and in 48% and 53% of patients with cPTmax >1.9 mm, p<0.001. Conclusions: This is the first study showing that cPTmax is increased in patients with chronic kidney disease stage 3 compared to controls and closely associated with prevalent cardiovascular disease and severity of calcification in both the carotid and coronary arteries. [ABSTRACT FROM AUTHOR]
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- 2021
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25. 18F-FDG PET Imaging of Murine Atherosclerosis: Association with Gene Expression of Key Molecular Markers.
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Hag, Anne Mette Fisker, Pedersen, Sune Folke, Christoffersen, Christina, Binderup, Tina, Jensen, Mette Munk, Jørgensen, Jesper Tranekjær, Skovgaard, Dorthe, Ripa, Rasmus Sejersten, and Kjaer, Andreas
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GENE expression , *BIOMARKERS , *ATHEROSCLEROSIS , *HYPOXEMIA , *MOLECULES , *CELL adhesion molecules - Abstract
Aim:To study whether 18F-FDG can be used for in vivo imaging of atherogenesis by examining the correlation between 18FFDG uptake and gene expression of key molecular markers of atherosclerosis in apoE-/- mice. Methods:Nine groups of apoE-/- mice were given normal chow or high-fat diet. At different time-points, 18F-FDG PET/ contrast-enhanced CT scans were performed on dedicated animal scanners. After scans, animals were euthanized, aortas removed, gamma counted, RNA extracted from the tissue, and gene expression of chemo (C-X-C motif) ligand 1 (CXCL-1), monocyte chemoattractant protein (MCP)-1, vascular cell adhesion molecule (VCAM)-1, cluster of differentiation molecule (CD)-68, osteopontin (OPN), lectin-like oxidized LDL-receptor (LOX)-1, hypoxia-inducible factor (HIF)-1α, HIF-2α, vascular endothelial growth factor A (VEGF), and tissue factor (TF) was measured by means of qPCR. Results:The uptake of 18F-FDG increased over time in the groups of mice receiving high-fat diet measured by PET and ex vivo gamma counting. The gene expression of all examined markers of atherosclerosis correlated significantly with 18F-FDG uptake. The strongest correlation was seen with TF and CD68 (p<0.001). A multivariate analysis showed CD68, OPN, TF, and VCAM-1 to be the most important contributors to the uptake of 18F-FDG. Together they could explain 60% of the 18F-FDG uptake. Conclusion:We have demonstrated that 18F-FDG can be used to follow the progression of atherosclerosis in apoE-/- mice. The gene expression of ten molecular markers representing different molecular processes important for atherosclerosis was shown to correlate with the uptake of 18F-FDG. Especially, the gene expressions of CD68, OPN, TF, and VCAM-1 were strong predictors for the uptake. [ABSTRACT FROM AUTHOR]
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- 2012
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26. Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL
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Elsøe, Sara, Ahnström, Josefin, Christoffersen, Christina, Hoofnagle, Andrew N., Plomgaard, Peter, Heinecke, Jay W., Binder, Christoph J., Björkbacka, Harry, Dahlbäck, Björn, and Nielsen, Lars B.
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APOLIPOPROTEINS , *PHOSPHOLIPIDS , *ANTIOXIDANTS , *HIGH density lipoproteins , *LOW density lipoproteins , *LABORATORY mice , *ATHEROSCLEROSIS - Abstract
Abstract: Objective: Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL. Methods and results: HDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ∼2-fold and ∼10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu2+ or 2,2′-azobis 2-methyl-propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM. Conclusions: The results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM. [Copyright &y& Elsevier]
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- 2012
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27. Oral pre-treatment with thiocyanate (SCN−) protects against myocardial ischaemia–reperfusion injury in rats.
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Hall, Luke, Guo, Chaouri, Tandy, Sarah, Broadhouse, Kathryn, Dona, Anthony C., Malle, Ernst, Bartels, Emil D., Christoffersen, Christina, Grieve, Stuart M., Figtree, Gemma, Hawkins, Clare L., and Davies, Michael J.
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THIOCYANATES , *MYOCARDIAL ischemia , *REPERFUSION injury , *MYOCARDIAL revascularization , *MYELOPEROXIDASE - Abstract
Despite improvements in revascularization after a myocardial infarction, coronary disease remains a major contributor to global mortality. Neutrophil infiltration and activation contributes to tissue damage, via the release of myeloperoxidase (MPO) and formation of the damaging oxidant hypochlorous acid. We hypothesized that elevation of thiocyanate ions (SCN−), a competitive MPO substrate, would modulate tissue damage. Oral dosing of rats with SCN−, before acute ischemia–reperfusion injury (30 min occlusion, 24 h or 4 week recovery), significantly reduced the infarct size as a percentage of the total reperfused area (54% versus 74%), and increased the salvageable area (46% versus 26%) as determined by MRI imaging. No difference was observed in fractional shortening, but supplementation resulted in both left-ventricle end diastolic and left-ventricle end systolic areas returning to control levels, as determined by echocardiography. Supplementation also decreased antibody recognition of HOCl-damaged myocardial proteins. SCN− supplementation did not modulate serum markers of damage/inflammation (ANP, BNP, galectin-3, CRP), but returned metabolomic abnormalities (reductions in histidine, creatine and leucine by 0.83-, 0.84- and 0.89-fold, respectively), determined by NMR, to control levels. These data indicate that elevated levels of the MPO substrate SCN−, which can be readily modulated by dietary means, can protect against acute ischemia–reperfusion injury. [ABSTRACT FROM AUTHOR]
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- 2021
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28. Neonatal HDL Counteracts Placental Vascular Inflammation via S1P–S1PR1 Axis.
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Del Gaudio, Ilaria, Hendrix, Sebastian, Christoffersen, Christina, and Wadsack, Christian
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HIGH density lipoproteins , *ANGIOTENSIN II , *INFLAMMATION , *CORD blood , *ENDOTHELIUM diseases , *ENDOTHELIAL cells , *ABRUPTIO placentae - Abstract
Placental inflammation and dysfunction during pregnancy are associated with short- and long-term adverse outcomes for the offspring. However, the mechanisms of vascular protection at the feto-placental interface are still poorly investigated. The high-density lipoprotein (HDL) associated sphingosine-1-phosphate (S1P) has been described as a powerful anti-inflammatory complex. This study aimed to elucidate the role of cord blood-derived HDL (nHDL) in feto-placental endothelial dysfunction. Here, we report that the exposure of primary fetal placental arterial endothelial cell (fPAEC) to healthy nHDL-S1P attenuated the ability of TNFα to activate NF-κB signaling and increase the expression of pro-inflammatory markers. Moreover, the angiotensin II (AngII)-induced reactive oxygen species (ROS) production was blunted in the presence of nHDL, whereas it was preserved when the cells were preincubated with S1P receptor antagonists, suggesting that S1P accounts for the vascular protective function of nHDL at the feto-placental unit. These results highlight the importance of HDL and S1P metabolism and signaling in pregnancy pathophysiology. [ABSTRACT FROM AUTHOR]
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- 2020
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29. Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding.
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Tian, E., Shengjun Wang, Liping Zhang, Ying Zhang, Malicdan, May C., Yang Mao, Christoffersen, Christina, Tabak, Lawrence A., Schjoldager, Katrine T., and Ten Hagen, Kelly G.
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LIGAND binding (Biochemistry) , *POST-translational modification , *KIDNEYS , *CHRONIC kidney failure , *PROTEIN stability - Abstract
Chronic kidney disease (CKD) affects more than 20 million Americans and ~10% of the population worldwide. Genome-wide association studies (GWAS) of kidney functional decline have identified genes associated with CKD, but the precise mechanisms by which they influence kidney function remained largely unexplored. Here, we examine the role of 1 GWAS-identified gene by creating mice deficient for Galnt11, which encodes a member of the enzyme family that initiates protein O-glycosylation, an essential posttranslational modification known to influence protein function and stability. We find that Galnt11-deficient mice display low-molecular-weight proteinuria and have specific defects in proximal tubule-mediated resorption of vitamin D binding protein, α1-microglobulin, and retinol binding protein. Moreover, we identify the endocytic receptor megalin (LRP2) as a direct target of Galnt11 in vivo. Megalin in Galnt11- deficient mice displays reduced ligand binding and undergoes agerelated loss within the kidney. Differential mass spectrometry revealed specific sites of Galnt11-mediated glycosylation within mouse kidney megalin/LRP2 that are known to be involved in ligand binding, suggesting that O-glycosylation directly influences the ability to bind ligands. In support of this, recombinant megalin containing these sites displayed reduced albumin binding in cells deficient for Galnt11. Our results provide insight into the association between GALNT11 and CKD, and identify a role for Galnt11 in proper kidney function. [ABSTRACT FROM AUTHOR]
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- 2019
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30. Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway.
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Ratner, Cecilia, Zhenyan He, Grunddal, Kaare V., Skov, Louise J., Hartmann, Bolette, Fa Zhang, Feuchtinger, Annette, Bjerregaard, Anette, Christoffersen, Christina, Tschöp, Matthias H., Finan, Brian, DiMarchi, Richard D., Leinninger, Gina M., Williams, Kevin W., Clemmensen, Christoffer, and Holst, Birgitte
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NEUROTENSIN , *BODY weight , *INGESTION , *OBESITY , *GASTROINTESTINAL hormones , *GLUCAGON-like peptides , *APPETITE stimulants - Abstract
Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a longacting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagonlike peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT–induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy. [ABSTRACT FROM AUTHOR]
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- 2019
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31. Diurnal regulation of sphingolipids in blood.
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Brunkhorst, Robert, Pfeilschifter, Waltraud, Rajkovic, Natasa, Pfeffer, Martina, Fischer, Claudia, Korf, Horst-Werner, Christoffersen, Christina, Trautmann, Sandra, Thomas, Dominique, Pfeilschifter, Josef, and Koch, Alexander
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SPHINGOLIPIDS , *HOMEOSTASIS , *CIRCADIAN rhythms , *LABORATORY mice , *BLOOD platelets , *CARRIER proteins , *TANDEM mass spectrometry - Abstract
Abstract Key homeostatic functions are regulated in a diurnal manner and a miss-alignment of such rhythms is believed to contribute to the pathophysiology of several diseases. Signaling sphingolipids (SLs) in plasma such as sphingosine 1-phosphate control lymphocytic trafficking, vascular reactivity and platelet activity, physiological functions all of which display a diurnal rhythm themselves. However, the rhythmicity of SL metabolism in plasma and its potential causes have not been sufficiently investigated so far. Therefore, we analyzed blood of mice and healthy adult human subjects by targeted tandem mass-spectrometry at different time points. In order to investigate the influence of the synchronizing hormone melatonin, we compared melatonin proficient C3H/HeN wildtype mice (C3H) with melatonin receptor-1/2 double knockout mice (MT1/2−/−) and melatonin deficient C57BL/6J mice. We found a strong upregulation of plasma S1P with the beginning of the light period in C3H but not in MT1/2−/− or C57BL/6J mice. Accordingly, our study revealed an upregulation of sphingosine 1-phosphate (S1P d18:1) and sphinganine 1-phosphate (S1P d18:0) with the beginning of the light period in humans. Furthermore, plasma S1P d18:1 and S1P d18:0 were inversely correlated with the respective concentrations in platelets, pointing to a possible involvement of platelet SL metabolism. In humans, the diurnal rhythm of SLs was not associated with changes of SL-binding proteins or counts of cellular SL sources. Overall, this study indicates a physiological rhythmicity of plasma and platelet SL metabolism, likely mediated by melatonin, with potentially important implications for physiological diurnal rhythms and the regulation of SL metabolism and its functions. Highlights • Sphingolipids are diurnally regulated in human and mouse plasma. • The diurnal regulation of sphingosine 1-phosphate and sphinganine 1-phosphate is dependent on intact melatonin signalling. • Sphingosine 1-phosphate in human plasma is associated by alterations of sphingosine 1-phosphate concentrations in platelets. • Sphingolipids in human plasma is independent of a regulation of sphingolipid chaperons and sphingolipid producing cells. [ABSTRACT FROM AUTHOR]
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- 2019
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32. Apolipoprotein M in patients with chronic kidney disease.
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Sørensen, Ida MH., Bertelsen, Marianne, Freese, Ellen, Lindhard, Kristine, Ullum, Henrik, Feldt-Rasmussen, Bo, Nielsen, Lars Bo, Christoffersen, Christina, and Bro, Susanne
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KIDNEY diseases , *APOLIPOPROTEINS , *HIGH density lipoproteins , *EXCRETION , *ENZYME-linked immunosorbent assay , *PATIENTS - Abstract
Background and aims Plasma apolipoprotein M (APOM) is bound to HDL-particles and has anti-atherogenic effects. The present study explored whether plasma APOM is reduced in patients with chronic kidney disease (CKD), and associated with cardiovascular disease (CVD). In addition, we tested the hypothesis that the excretion of APOM into the urine is increased in patients with kidney disease. Methods Plasma samples were collected from a cohort of patients with CKD stages 1 to 5D (N = 409) and controls (N = 35). Urine was collected from 47 subjects. Plasma APOM was measured with sandwich ELISA and urine APOM with competitive ELISA. Results Plasma APOM levels were reduced in patients with CKD stages 3-5D as compared to patients with CKD stages 1 + 2 and controls ( p < 0.01). CKD patients with known CVD displayed even further reduction in plasma APOM levels than CKD patients without known CVD ( p < 0.001). Fast-phase liquid chromatography showed that plasma APOM was primarily associated with HDL-cholesterol (HDL-C) across CKD stages. Accordingly, when plasma APOM values were corrected for HDL-C, a significant difference only persisted between patients with CKD stage 3 and stages 1 + 2 ( p < 0.05), and the difference between CKD patients with and without known CVD disappeared. Urine APOM/creatinine ratio was not significantly increased in patients with kidney disease. Conclusions The results show that the difference in plasma APOM levels observed between patients with mild and advanced CKD may mainly be due to differences in plasma HDL-C. Whether APOM plays a role in human uremic atherogenesis warrants further experimental studies. [ABSTRACT FROM AUTHOR]
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- 2018
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33. Evaluation of image quality and radiation dose of abdominal dual-energy CT.
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Schmidt, David, Söderberg, Marcus, Nilsson, Mats, Lindvall, Håkan, Christoffersen, Christina, and Leander, Peter
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COMPUTED tomography , *RADIATION , *IMAGE quality analysis , *CLINICAL trials , *ABDOMINAL abnormalities - Abstract
Background Dual-energy computed tomography (DECT) has conceptually been known since the late 1970s and commercially available as dual-source CT (DSCT) systems since 2006; however, the technique has not yet seen widespread implementation in routine protocols. Part of the cause for this is likely due to misconceptions about radiation dose and/or image quality when using DECT. Purpose To compare image quality and radiation dose of single-energy CT (SECT) and DECT abdominal examinations obtained in clinical practice on a second generation DSCT. Material and Methods A total of 495 included patients (mean age = 70.9 years) were retrospectively analyzed after undergoing either SECT (120 kVp and age-based mAs) or DECT examinations (80/Sn140 kVp and age-based mAs). The patients were divided into two groups based on examination type (247 SECT, 248 DECT), which were then subdivided into two groups, each based on age. Image noise was measured in the liver and image quality was subjectively assessed in 100 randomly selected patients. Results Noise levels were significantly lower in DECT (13.9 HU) compared with SECT (14.7 HU) ( P < 0.05). No significant differences in subjective image quality were found between DECT and SECT, except for one criterion in the 50-74-year age group. The mean dose-length product (DLP) (376 mGy-cm) and effective dose (6.1 mSv) of DECT were significantly lower than the DLP (513 mGy-cm) and effective dose (8.4 mSv) of SECT ( P < 0.05). Conclusion DECT can be implemented in routine clinical use without negatively impacting image quality while lowering radiation dose to the patient. [ABSTRACT FROM AUTHOR]
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- 2018
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34. Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions.
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Shengjun Wang, Yang Mao, Yoshiki Narimatsu, Zilu Ye, Weihua Tian, Goth, Christoffer K., Lira-Navarrete, Erandi, Pedersen, Nis B., Benito-Vicente, Asier, Martin, Cesar, Uribe, Kepa B., Hurtado-Guerrero, Ramon, Christoffersen, Christina, Seidah, Nabil G., Nielsen, Rikke, Christensen, Erik I., Hansen, Lars, Bennett, Eric P., Vakhrushev, Sergey Y., and Schjoldager, Katrine T.
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GLYCOSYLATION , *LOW density lipoproteins , *G protein coupled receptors , *DRUG development , *LIPOPROTEIN receptors - Abstract
The low-density lipoprotein receptor (LDLR) and related receptors are important for the transport of diverse biomolecules across cell membranes and barriers. Their functions are especially relevant for cholesterol homeostasis and diseases, including neurodegenerative and kidney disorders. Members of the LDLR-related protein family share LDLR class A (LA) repeats providing binding properties for lipoproteins and other biomolecules. We previously demonstrated that short linker regions between these LA repeats contain conserved O-glycan sites. Moreover, we found that O-glycan modifications at these sites are selectively controlled by the GalNAc-transferase isoform, GalNAc-T11. However, the effects of GalNAc-T11- mediated O-glycosylation on LDLR and related receptor localization and function are unknown. Here, we characterized O-glycosylation of LDLR-related proteins and identified conserved O-glycosylation sites in the LA linker regions of VLDLR, LRP1, and LRP2 (Megalin) from both cell lines and rat organs. Using a panel of gene-edited isogenic cell line models, we demonstrate that GalNAc-T11-mediated LDLR and VLDLR O-glycosylation is not required for transport and cell-surface expression and stability of these receptors but markedly enhances LDL and VLDL binding and uptake. Direct ELISA-based binding assays with truncated LDLR constructs revealed that O-glycosylation increased affinity for LDL by ~5-fold. The molecular basis for this observation is currently unknown, but these findings open up new avenues for exploring the roles of LDLR-related proteins in disease. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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35. CHRONIC KIDNEY DISEASE AETIOLOGY'S EFFECT ON CARDIAC STRUCTURE AND FUNCTION: THE CPH-CKD ECHO STUDY.
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Christensen, Jacob, Landler, Nino Emanuel, Olsen, Flemming Javier, Soerensen, Ida Maria Hjelm, Bjergfelt, Sasha Saurbrey, Bro, Susanne, Feldt-Rasmussen, Bo, Hansen, Ditte, Kamper, Anne-Lise, Christoffersen, Christina, and Biering-Sorensen, Tor
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CHRONIC kidney failure - Published
- 2023
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36. High density lipoprotein (HDL)-associated sphingosine 1-phosphate (S1P) inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression.
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Feuerborn, Renata, Becker, Susen, Potì, Francesco, Nagel, Petra, Brodde, Martin, Schmidt, Harmut, Christoffersen, Christina, Ceglarek, Uta, Burkhardt, Ralph, and Nofer, Jerzy-Roch
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HIGH density lipoproteins , *SPHINGOSINE-1-phosphate , *MACROPHAGES , *APOPTOSIS , *SURVIVIN (Protein) - Abstract
Background and aims Macrophage apoptosis is critically involved in atherosclerosis. We here examined the effect of anti-atherogenic high density lipoprotein (HDL) and its component sphingosine-1-phosphate (S1P) on apoptosis in RAW264.7 murine macrophages. Methods Mitochondrial or endoplasmic reticulum-dependent apoptosis was induced by exposure of macrophages to etoposide or thapsigargin/fukoidan, respectively. Results Cell death induced by these compounds was inhibited by S1P as inferred from reduced annexin V binding, TUNEL staining, and caspase 3, 9 and 12 activities. S1P induced expression of the inhibitor of apoptosis protein (IAP) family proteins cIAP1, cIAP2 and survivin, but only the inhibitor of survivin expression YM155 and not the cIAP1/2 blocker GDC0152 reversed the inhibitory effect of S1P on apoptosis. Moreover, S1P activated signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2 (JAK2) and the stimulatory effect of S1P on survivin expression and inhibitory effects on apoptosis were attenuated by STAT3 or JAK2 inhibitors, S3I-201 or AG490, respectively. The effects of S1P on STAT3 activation, survivin expression and macrophage apoptosis were emulated by HDL, HDL lipids, and apolipoprotein (apo) M-containing HDL, but not by apoA-I or HDL deprived of S1P or apoM. In addition, JTE013 and CAY10444, S1P receptor 2 and 3 antagonists, respectively, compromised the S1P and HDL capacities to stimulate STAT3 activation and survivin expression, and to inhibit apoptosis. Conclusions HDL-associated S1P inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression. The suppression of macrophage apoptosis may represent a novel mechanism utilized by HDL to exert its anti-atherogenic effects. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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37. Familial hypercholesterolaemia: cholesterol efflux and coronary disease.
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Versmissen, Jorie, Vongpromek, Ranitha, Yahya, Reyhana, Net, Jeroen B., Vark‐van der Zee, Leonie, Blommesteijn‐Touw, Jeannette, Wattimena, Darcos, Rietveld, Trinet, Pullinger, Clive R., Christoffersen, Christina, Dahlbäck, Björn, Kane, John P., Mulder, Monique, and Sijbrands, Eric J. G.
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GENETIC disorders , *CHOLESTEROL , *CORONARY disease , *HIGH density lipoproteins , *APOLIPOPROTEINS - Abstract
Background Coronary heart disease ( CHD) risk inversely associates with levels of high-density lipoprotein cholesterol ( HDL-C). The protective effect of HDL is thought to depend on its functionality, such as its ability to induce cholesterol efflux. Materials and methods We compared plasma cholesterol efflux capacity between male familial hypercholesterolaemia ( FH) patients with and without CHD relative to their non- FH brothers, and examined HDL constituents including sphingosine-1-phosphate (S1P) and its carrier apolipoprotein M (apoM). Results Seven FH patients were asymptomatic and six had experienced a cardiac event at a mean age of 39 years. Compared to their non- FH brothers, cholesterol efflux from macrophages to plasma from the FH patients without CHD was 16 ± 22% (mean ± SD) higher and to plasma from the FH patients with CHD was 7 ± 8% lower ( P = 0·03, CHD vs. non- CHD). Compared to their non- FH brothers, FH patients without CHD displayed significantly higher levels of HDL-cholesterol, HDL-S1P and apoM, while FH patients with CHD displayed lower levels than their non- FH brothers. Conclusions A higher plasma cholesterol efflux capacity and higher S1P and apoM content of HDL in asymptomatic FH patients may play a role in their apparent protection from premature CHD. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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38. Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1.
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Christensen, Pernille M., Liu, Catherine H., Swendeman, Steven L., Obinata, Hideru, Qvortrup, Klaus, Nielsen, Lars B., Hla, Timothy, Di Lorenzo, Annarita, and Christoffersen, Christina
- Abstract
Apolipoprotein M (ApoM) transports sphingosine-1-phosphate (S1P) in plasma, and ApoM-deficient mice (Apom-/-) have ~50% reduced plasma S1P levels. There are 5 known S1P receptors, and S1P induces adherens junction formation between endothelial cells through the S1P1 receptor, which in turn suppresses vascular leak. Increased vascular permeability is a hallmark of inflammation. The purpose of this study was to explore the relationships between vascular leakage in ApoM deficiency and S1P1 function in normal physiology and in inflammation. Vascular permeability in the lungs was assessed by accumulation of dextran molecules (70 kDa) and was increased ~40% in Apom-/- mice compared to WT (C57Bl6/j) mice. Reconstitution of plasma ApoM/S1P or treatment with an S1P1 receptor agonist (SEW2871) rapidly reversed the vascular leakage to a level similar to that in WT mice, suggesting that it is caused by decreased plasma levels of S1P and reduced S1P1 stimulation. In a carrageenan-induced model of inflammation, Apom-/- mice had increased vascular leakage compared with that in WT mice. Adenoviral overexpression of ApoM in Apom-/- mice decreased the vascular leakage compared to adenoviral overexpression of green fluorescent protein. The study suggests that vascular leakage of albumin-sized particles in ApoM deficiency is S1P- and S1P1-dependent and this dependency exacerbates the response to inflammatory stimuli. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
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39. Association between plasma apolipoprotein M and cardiac autonomic neuropathy in type 1 diabetes.
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Safi, Mostafa, Borup, Anna, Stevns Hansen, Christian, Rossing, Peter, Thorsten Jensen, Magnus, and Christoffersen, Christina
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TYPE 1 diabetes , *NEUROPATHY , *HEART beat , *ODDS ratio , *BLOOD pressure , *APOLIPOPROTEIN E4 , *DISEASE complications - Abstract
Aim: Diabetes may lead to severe complications e.g. cardiac autonomic neuropathy (CAN) characterized by an increased risk of cardiovascular mortality. CAN is diagnosed by a decreased heart rate viability (HRV). Sphingosine-1-Phosphate (S1P) carried by the HDL-associated apolipoprotein M (apoM) is linked to a reduction in the heart rate, and treatment with an S1P-agonist increases HRV. The present study aimed to investigate if plasma apoM was associated with an increased risk of CAN.Methods: The study includes 278 individuals with Type 1 Diabetes recruited from Steno Diabetes Center in Copenhagen from 2010 to 2012.Results: A change of 0.1 µM plasma apoM was associated with the diagnosis of CAN (Odds ratio: 1.11 (1.02; 1.21), p = 0.013). ApoM plasma levels were also positively associated with CAN when adjusted for age and gender (Odds ratio: 1.11 (1.02; 1.21), p = 0.013) as well as lipids, beta-blockers, blood pressure, and alcohol (Odds ratio: 1.14 (1.04; 1.26), p = 0.005) and Hbga1c and time with diabetes (Odds ratio: 1.13 (1.02; 1.25), p = 0.01). Plasma apoM was also associated with a significantly lower SDNN as well as high frequency power in all adjusted models.Conclusion: Increased plasma apoM was associated with an increased risk of CAN as well as a significant reduction in HRV indices. This could represent changes in parasympathetic activity, but, further studies are needed to also explore additional molecular alterations behind such observations. [ABSTRACT FROM AUTHOR]- Published
- 2022
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40. Osteopontin deficiency dampens the pro-atherogenic effect of uraemia.
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Pedersen, Tanja X., Madsen, Marie, Junker, Nanna, Christoffersen, Christina, Vikeså, Jonas, Bro, Susanne, Hultgårdh-Nilsson, Anna, and Nielsen, Lars Bo
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OSTEOPONTIN , *UREMIA , *CARDIOVASCULAR diseases risk factors , *LABORATORY mice , *ATHEROSCLEROSIS , *GENE expression , *MACROPHAGES - Abstract
Aims Uraemia is a strong risk factor for cardiovascular disease. Osteopontin (OPN) is highly expressed in aortas of uraemic apolipoprotein E knockout (E KO) mice. OPN affects key atherogenic processes, i.e. inflammation and phenotypic modulation of smooth muscle cells (SMCs). We explored the role of OPN on vascular pathology in uraemic mice. Methods and results Uraemia was induced by 5/6 nephrectomy in E KO and in OPN and E double KO mice (E/OPN KO). In E KO mice, uraemia increased the relative surface plaque area in the aortic arch (from 28 ± 2% [n = 15], to 37 ± 3% [n = 20] of the aortic arch area, P < 0.05). A positive correlation was observed between plasma OPN and aortic atherosclerosis in uraemic E KO mice (r2 = 0.48, P = 0.001). In contrast, aortic atherosclerosis was not increased by uraemia in E/OPN KO mice. OPN deficiency in haematopoietic cells (including macrophages) did not affect development of uraemic atherosclerosis, even though OPN-deficient foam cells had decreased inflammatory capacity. Gene expression analyses indicated that uraemia de-differentiates SMCs in the arterial wall. This effect was dampened in whole-body OPN-deficient mice. Conclusion The data suggest that OPN promotes development of uraemic atherosclerosis possibly by changing the phenotype of vascular smooth muscle cells. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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41. The Apolipoprotein M--Sphingosine-1-Phosphate Axis: Biological Relevance in Lipoprotein Metabolism, Lipid Disorders and Atherosclerosis.
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Arkensteijn, Bas W. C., Berbée, Jimmy F. P., Rensen, Patrick C. N., Nielsen, Lars B., and Christoffersen, Christina
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APOLIPOPROTEINS , *ATHEROSCLEROSIS , *HIGH density lipoproteins , *G proteins , *NEOVASCULARIZATION , *SPHINGOSINE-1-phosphate , *LIPOPROTEINS - Abstract
Apolipoprotein M (apoM) is a plasma apolipoprotein that mainly associates with high-density lipoproteins. Hence, most studies on apoM so far have investigated its effect on and association with lipid metabolism and atherosclerosis. The insight into apoM biology recently took a major turn. ApoM was identified as a carrier of the bioactive lipid sphingosine-1-phosphate (S1P). S1P activates five different G-protein-coupled receptors, known as the S1P-receptors 1-5 and, hence, affects a wide range of biological processes, such as lymphocyte trafficking, angiogenesis, wound repair and even virus suppression and cancer. The ability of apoM to bind S1P is due to a lipophilic binding pocket within the lipocalin structure of the apoM molecule. Mice overexpressing apoM have increased plasma S1P concentrations, whereas apoM-deficient mice have decreased S1P levels. ApoM-S1P is able to activate the S1P-receptor-1, affecting the function of endothelial cells, and apoM-deficient mice display impaired endothelial permeability in the lung. This review will focus on the putative biological roles of the new apoM--S1P axis in relation to lipoprotein metabolism, lipid disorders and atherosclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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42. Impaired LDL Receptor-Related Protein 1 Translocation Correlates with Improved Dyslipidemia and Atherosclerosis in apoE-Deficient Mice.
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Gordts, Philip L. S. M., Bartelt, Alexander, Nilsson, Stefan K., Annaert, Wim, Christoffersen, Christina, Nielsen, Lars Bo, Heeren, Joerg, and Roebroek, Anton J. M.
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WASTE recycling , *LOW density lipoproteins , *CHROMOSOMAL translocation , *CHROMOSOMES , *GENETICS - Abstract
Objective: Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE. Methods and Results: LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with apoEdeficient mice. In the absence of apoE, relative to LRP1 wild-type animals, LRP1 mutated mice showed an increased clearance of postprandial lipids despite a compromised LRP1 endocytosis rate and inefficient insulin-mediated translocation of the receptor to the plasma membrane, likely due to inefficient slow recycling of the mutated receptor. Postprandial lipoprotein improvement was explained by increased hepatic clearance of triglyceride-rich remnant lipoproteins and accompanied by a compensatory 1.6-fold upregulation of LDLR expression in hepatocytes. One year-old apoE-deficient mice having the dysfunctional LRP1 revealed a 3-fold decrease in spontaneous atherosclerosis development and a 2-fold reduction in LDL-cholesterol levels. Conclusion: These findings demonstrate that the NPxYxxL motif in LRP1 is important for insulin-mediated translocation and slow perinuclear endosomal recycling. These LRP1 impairments correlated with reduced atherogenesis and cholesterol levels in apoE-deficient mice, likely via compensatory LDLR upregulation. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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43. Increased plasma apoM levels impair triglyceride turnover in mice.
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Hajny, Stefan, Borup, Anna, Elsøe, Sara, and Christoffersen, Christina
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HIGH density lipoproteins , *BROWN adipose tissue , *TRIGLYCERIDES , *LABORATORY mice , *FREE fatty acids , *LIPASES - Abstract
Apolipoprotein M (apoM) is an essential transporter of plasma Sphingosine-1-Phosphate (S1P), typically attached to all lipoprotein classes, but with a majority bound to high density lipoproteins (HDL). ApoM-deficient mice display an increased activity in brown adipose tissue and a concomitant fast turnover of triglycerides. In what manner apoM/S1P affect the triglyceride metabolism is however still unknown and explored in the present study. Triglyceride turnover and potentially associated metabolic pathways were studied in the female human apoM transgenic mouse model (apoM-Tg) with increased plasma apoM and S1P levels. The model was compared with wild type (WT) mice. ApoM-Tg mice had a reduced plasma triglyceride turnover rate and a lower free fatty acid uptake in subcutaneous adipocytes compared to WT mice. Screening for potential molecular mechanisms furthermore revealed a reduction in plasma lipase activity in apoM-Tg animals. Overexpression of apoM also reduced the plasma levels of fibroblast growth factor 21 (FGF21). The study features the significant role of the apoM/S1P axis in maintaining a balanced triglyceride metabolism. Further, it also highlights the risk of inducing dyslipidaemia in patients receiving S1P-analouges and additionlly emphasizes the apoM/S1P axis as a potential therapeutic target in treatment of hypertriglyceridemia. • Plasma triglyceride turnover in apoM-Tg mice is substantially decelerated • Increased apoM/S1P concentrations reduce plasma lipase activities • Elevated plasma apoM/S1P levels decrease plasma FGF21 • ApoM-Tg mice display changes in syndecan expression and shedding [ABSTRACT FROM AUTHOR]
- Published
- 2021
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44. Effect of insulin on natriuretic peptide gene expression in porcine heart.
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Terzic, Dijana, Zois, Nora E., Hunter, Ingrid, Christoffersen, Christina, Plomgaard, Peter, Olsen, Lisbeth Høier, Ringholm, Stine, Pilegaard, Henriette, and Goetze, Jens P.
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LEFT heart ventricle , *INSULIN , *GENE expression , *GASTROINTESTINAL hormones , *INSULIN receptors , *HYPERINSULINISM - Abstract
• Acute euglycemic hyperinsulinemia activates Akt signalling pathway in the porcine myocardium. • BNP mRNA content in the left ventricle decreased following acute euglycemic hyperinsulinemia. • No changes in ANP mRNA contents were demonstrated as a result of insulin infusion. • Acute euglycemic hyperinsulinemia was not associated with changes in circulating proANP concentrations. Gut hormones affect cardiac function and contractility. In this study, we examined whether insulin affects the cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression and release of proANP-derived peptides in pigs. Anaesthetized pigs were included in an experimental study comparing the effect of hyperinsulinemia in 15 pigs submitted to two different protocols versus 11 control pigs receiving saline infusion. Phosphorylation of Akt on Thr308 was determined by western blotting with a pAkt-Thr308 antibody. The mRNA contents of ANP and BNP were determined with real-time PCR; plasma and cardiac tissue proANP was measured with an immunoluminometric assay targeted against the mid-region of the propeptide and a processing-independent assay. Insulin stimulation increased phosphorylation of Akt Thr308 in both left atrium and left ventricle of porcine hearts (p < 0.005). No change was observed in ANP and BNP mRNA contents in the right or left atrium. BNP mRNA contents in the left ventricle, however, decreased 3-fold (p = 0.02) compared to control animals, whereas the BNP mRNA content in the right ventricle as well as ANP mRNA content in the right and left ventricle did not change following hyperinsulinemia. Moreover, the peptide contents did not change in the four cardiac chambers. Finally, proANP concentrations in plasma did not change during the insulin infusion compared to the control animals. These results suggest that insulin does not have direct effect on atrial natriuretic peptide expression but may have a role in the left ventricle. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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45. Aging Suppresses Sphingosine-1-Phosphate Chaperone ApoM in Circulation Resulting in Maladaptive Organ Repair.
- Author
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Ding, Bi-Sen, Yang, Dawei, Swendeman, Steve L., Christoffersen, Christina, Nielsen, Lars B., Friedman, Scott L., Powell, Charles A., Hla, Timothy, and Cao, Zhongwei
- Subjects
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SPHINGOSINE-1-phosphate , *VASCULAR endothelial cells , *TRANSGENIC mice , *INFUSION therapy , *PULMONARY fibrosis - Abstract
Here, we show that the liver-derived apolipoprotein M (ApoM) protects the lung and kidney from pro-fibrotic insults and that this circulating factor is attenuated in aged mice. Aged mouse hepatocytes exhibit transcriptional suppression of ApoM. This leads to reduced sphingosine-1-phosphate (S1P) signaling via the S1P receptor 1 (S1PR1) in the vascular endothelial cells of lung and kidney. Suboptimal S1PR1 angiocrine signaling causes reduced resistance to injury-induced vascular leak and leads to organ fibrosis. Plasma transfusion from Apom transgenic mice but not Apom knockout mice blocked fibrosis in the lung. Similarly, infusion of recombinant therapeutics, ApoM-Fc fusion protein enhanced kidney and lung regeneration and attenuated fibrosis in aged mouse after injury. Furthermore, we identified that aging alters Sirtuin-1-hepatic nuclear factor 4α circuit in hepatocytes to downregulate ApoM. These data reveal an integrative organ adaptation that involves circulating S1P chaperone ApoM+ high density lipoprotein (HDL), which signals via endothelial niche S1PR1 to spur regeneration over fibrosis. • Liver-derived ApoM protects the lung and kidney from injuries • ApoM is lower in aged mice, causing reduced S1P signaling • Transfusion of plasma from Apom transgenic mice blocked fibrosis in the old lung • Recombinant ApoM-Fc fusion protein mitigated fibrosis in aged mouse lung and kidney Ding et al. show that liver-derived apolipoprotein M (ApoM) protects the lung and kidney from pro-fibrotic insults. Lower level of circulating ApoM in old animals causes scar formation in the injured lung and kidney. Injection of ApoM or ApoM-high blood component prevents lung and kidney from injury in old mice. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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46. Circulating cord blood HDL-S1P complex preserves the integrity of the feto-placental vasculature.
- Author
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Del Gaudio, Ilaria, Sreckovic, Ivana, Zardoya-Laguardia, Pablo, Bernhart, Eva, Christoffersen, Christina, Frank, Saša, Marsche, Gunther, Illanes, Sebastian E., and Wadsack, Christian
- Subjects
- *
CORD blood , *HIGH density lipoproteins , *EXTRACELLULAR signal-regulated kinases , *PHOSPHOLIPASES , *BLOOD circulation , *VASCULAR endothelium , *PHOSPHOLIPASE C , *PREGNANCY proteins - Abstract
Perinatal and long-term offspring morbidities are strongly dependent on the preservation of placental vascular homeostasis during pregnancy. In adults, the HDL-apoM-S1P complex protects the endothelium and maintains vascular integrity. However, the metabolism and biology of cord blood-derived HDLs (referred to as neonatal HDL, nHDL) strikingly differ from those in adults. Here, we investigate the role of neonatal HDLs in the regulation of placental vascular function. We show that nHDL is a major carrier of sphingosine-1-phosphate (S1P), which is anchored to the particle through apoM (rs = 0.90, p < 0.0001) in the fetal circulation. Furthermore, this complex interacts with S1P receptors on the feto-placental endothelium and activates specifically extracellular signal-regulated protein kinases 1 and 2 (ERK) and phospholipase C (PLC) downstream signaling, promotes endothelial cell proliferation and calcium flux. Notably, the nHDL-S1P complex triggers actin filaments reorganization, leading to an enhancement of placental endothelial barrier function. Additionally, nHDL induces vasorelaxation of isolated placental chorionic arteries. Taken together, these results suggest that circulating nHDL exerts vasoprotective effects on the feto-placental endothelial barrier mainly via S1P signaling. • ApoM acts as a chaperone to transport S1P on neonatal HDLs in cord blood circulation • nHDL-S1P promotes placental endothelial function by eliciting ERK and PLC pathways via S1PR1 activation • nHDL-S1P interaction with S1PR1 leads to enhancement of feto-placental endothelial barrier function • nHDL regulates placental vascular tone [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
47. Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway.
- Author
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Ratner, Cecilia, He, Zhenyan, Grunddal, Kaare V, Skov, Louise J, Hartmann, Bolette, Zhang, Fa, Feuchtinger, Annette, Bjerregaard, Anette, Christoffersen, Christina, Tschöp, Matthias H, Finan, Brian, DiMarchi, Richard D, Leinninger, Gina M, Williams, Kevin W, Clemmensen, Christoffer, and Holst, Birgitte
- Abstract
Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT-induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
48. P-79 - Effects of a novel selenosugar on primary human vascular cells, mouse aortic rings and atherosclerosis in apoE-/- mice.
- Author
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Zacharias, Triantafyllos, Flouda, Konstantina, Jepps, Thomas, Christoffersen, Christina, Pedersen, Tanja, Gammelgaard, Bente, Schiesser, Carl, and Davies, Michael
- Subjects
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ATHEROSCLEROSIS , *INFLAMMATION - Abstract
Atherosclerosis is characterized by chronic low-grade inflammation, large numbers of activated leukocytes, and the deposition of cholesterol and lipids in the artery wall. This project has investigated a novel seleno-sugar (1,4-anhydro-4-seleno-D-talitol, SeTal) as a potential regulator of oxidative stress, inflammation and atherosclerosis. SeTal did not affect the viability of human coronary artery endothelial and smooth muscle cells at low mM concentrations, or modulate thioredoxin reductase 1 or glutathione peroxidase 1 activity or levels. Concurrent or pre-treatment of cells with SeTal protected against toxicity induced by H 2 O 2 or HOCl. Studies on murine aortic rings showed that high concentrations of SeTal alone induced aortic relaxation on long-term treatment, and preserved endothelial cell-dependent relaxation on exposure to 50 µM HOCl. Oral dosing with SeTal (via drinking water) of apoE-/- mice did not affect weight gain, water consumption, or animal welfare. Intact SeTal was detected in plasma, liver and kidneys at micromolar levels. Plasma total cholesterol, triglycerides, and the inflammatory markers MCP-1, IL-6 and SAA were unaffected. The effects of SeTal on arterial atherosclerotic plaque size and composition will be presented. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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