| 1. |
- Jernås, Margareta, 1961, et al.
(författare)
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Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression
- 2006
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Ingår i: The FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6+-3.54 um) and large cells (mean 100.1+-3.94 um). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune-related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real-time RT-PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19-fold and 22-fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.
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| 2. |
- Sjöberg, Sara, 1979, et al.
(författare)
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CD44-deficiency on hematopoietic cells limits T-cell number but does not protect against atherogenesis in LDL receptor-deficient mice
- 2009
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 206:2, s. 369-374
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Vascular and inflammatory cells express adhesion molecule CD44. We demonstrated previously that enhanced CD44 localizes in human atherosclerotic lesions. Apolipoprotein E/cd44 double-deficient mice and apolipoprotein E-deficient mice transplanted with CD44-deficient bone marrow (BM) exhibit reduced atherosclerosis. Since CD44 is a novel factor in atherogenesis, it is imperative that it is investigated in more than one animal model to conclusively determine its role in this particular disease pathology. To test the hypothesis that CD44 expressed by hematopoietic cells plays a critical role in atherogenesis in the low density lipoprotein (LDL) receptor-deficient mouse model, we performed BM reconstitution experiments.METHODS: Lethally irradiated LDL receptor-deficient mice were transplanted with either CD44-deficient or wild-type BM. Beginning 10 weeks after successful reconstitution, mice consumed a cholesterol-enriched atherogenic diet for 6 or 11 weeks.RESULTS: Surprisingly, CD44-deficiency on BM-derived inflammatory cells did not affect lesion size. Additionally, neither group displayed differences in smooth muscle cell, macrophage, collagen, or elastin content as well as lipoprotein levels. However, lesions in CD44-deficient BM-recipient mice contained fewer T-cells compared to wild-type BM mice. Interestingly, CD44-deficient T-cells expressed less chemokine receptor-5 mRNA. Furthermore, in vivo leukocyte adhesion decreased in CD44-deficient mice compared to wild-type mice.CONCLUSION: This study surprisingly revealed that atherogenesis does not require CD44 expression on hematopoietic cells in the LDL receptor-deficient mouse model. However, CD44 promotes T-cell recruitment, downregulates chemokine receptor-5, and participates critically in leukocyte adhesion in vivo. Consequently, the anti-atherogenic role of CD44 may require CD44-deficiency on cell types other than inflammatory cells in the LDL receptor-deficient mouse model.
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| 3. |
- Leppanen, Olli, et al.
(författare)
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ATP depletion in macrophages in the core of advanced rabbit atherosclerotic plaques in vivo
- 2006
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Ingår i: Atherosclerosis. ; 188:2, s. 323-30
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Tidskriftsartikel (refereegranskat)abstract
- The cores of rabbit plaques in vivo are hypoxic, suggesting that ATP depletion due to an insufficient supply of oxygen and nutrients could contribute to macrophage death in atherosclerotic plaques. During hypoxia, however, macrophages maintain ATP levels by anaerobic glycolysis. To directly assess ATP and glucose metabolites in plaques in vivo, we used bioluminescence imaging to map the concentrations of ATP, glucose, glycogen, and lactate in normal and atherosclerotic rabbit aortas in vivo. Hypoxia was assessed with NITP (7-(4'-(2-nitroimidazol-1-yl)-butyl)-theophylline). Normal aortas and plaques <500 microm thick were not hypoxic and had homogenous concentrations of energy metabolites. In plaques >500 microm thick, however, the cores were characterized by ATP depletion, low concentrations of glucose and glycogen, and a high concentration of lactate. A majority of ATP-depleted macrophages within the core were viable but severely hypoxic and glucose depleted. Hyperoxia in vitro reversed the ATP depletion in macrophages in viable areas of the core. Our findings suggest that ATP depletion contributes to the death of macrophages in atherosclerotic lesions and to the formation of a necrotic core.
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| 4. |
- Levin, Max, 1969, et al.
(författare)
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ATP depletion and cell death in the neonatal lamb ductus arteriosus
- 2005
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Ingår i: Pediatr Res. - 0031-3998. ; 57:6, s. 801-805
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Tidskriftsartikel (refereegranskat)abstract
- Postnatal constriction of the full-term ductus arteriosus produces cell death and remodeling of the ductus wall. Using a bioluminescence imaging technique, we found that after birth, the lamb ductus develops ATP, glucose, and glycogen depletion in addition to hypoxia. In vitro studies showed that cell death correlates best with ATP depletion and is most marked when both glucose and oxygen are severely depleted; in addition, the degree of ATP depletion found in vivo is sufficient to account for the extensive degree of cell death that occurs after birth. Under hypoxic conditions, the immature ductus is more capable of preserving its ATP supply than the mature ductus as a result of increased glucose availability, glycogen stores, and glucose utilization. However, the immature ductus is just as susceptible as the mature ductus to ATP depletion when glucose supplies are restricted. The extensive degree of cell death that occurs in the newborn ductus after birth is associated primarily with ATP depletion. The increased glycolytic capacity of the immature ductus may enable it to tolerate episodes of hypoxia and nutrient shortage, making it more resistant to developing postnatal cell death and permanent closure.
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| 5. |
- Levin, Max, 1969, et al.
(författare)
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Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus
- 2006
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Ingår i: Am J Physiol Regul Integr Comp Physiol. - : American Physiological Society. - 0363-6119. ; 290:2
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Tidskriftsartikel (refereegranskat)abstract
- After birth, constriction of the full-term ductus arteriosus induces oxygen, glucose and ATP depletion, cell death, and anatomic remodeling of the ductus wall. The immature ductus frequently fails to develop the same degree of constriction or anatomic remodeling after birth. In addition, the immature ductus loses its ability to respond to vasoconstrictive agents, like oxygen or indomethacin, with increasing postnatal age. We examined the effects of premature delivery and postnatal constriction on the immature baboon ductus arteriosus. By 6 days after birth, surrogate markers of hypoxia (HIF1alpha/VEGF mRNA) and cell death [dUTP nick-end labeling (TUNEL)-staining] increased, while glucose and ATP concentrations (bioluminescence imaging) decreased in the immature ductus. TUNEL-staining was significantly related to the degree of glucose and ATP depletion. Glucose and ATP depletion were directly related to the degree of ductus constriction; while TUNEL-staining was logarithmically related to the degree of ductus constriction. Extensive cell death (>15% TUNEL-positive cells) occurred only when there was no Doppler flow through the ductus lumen. In contrast, HIF1alpha/VEGF expression and ATP concentrations were significantly altered even when the immature ductus remained open after birth. Decreased ATP concentrations produced decreased oxygen-induced contractile responses in the immature ductus. We hypothesize that ATP depletion in the persistently patent immature newborn ductus is insufficient to induce cell death and remodeling but sufficient to decrease its ability to constrict after birth. This may explain its decreasing contractile response to oxygen, indomethacin, and other contractile agents with increasing postnatal age.
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| 6. |
- Mattsson Hultén, Lillemor, 1951, et al.
(författare)
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The role of hypoxia in atherosclerosis
- 2009
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Ingår i: Current Opinion in Lipidology. - 0957-9672. ; 20:5, s. 409-414
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Forskningsöversikt (refereegranskat)
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| 7. |
- Solem, Jens, 1961, et al.
(författare)
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Composition of coronary plaques obtained by directional atherectomy in stable angina: its relation to serum lipids and statin treatment
- 2006
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Ingår i: J Intern Med. ; 259:3, s. 267-75
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The stability and inflammatory activity in atherosclerotic plaques may be modulated by lipids and lipoproteins as well as the pleiotropic effects of statins. The aim of this study was to analyse the effect of statin treatment as well as the relation of plasma lipids and lipoproteins to tissue composition in atherosclerotic plaques. DESIGN: Patients with stable angina and coronary plaques suitable for directional coronary atherectomy (DCA) were randomized to atorvastatin (80 mg once daily) or placebo (29 randomized, 22 underwent DCA, 11/group). After an average treatment of 10 weeks, patients underwent DCA, tissue specimens were obtained, and the tissue composition was determined by immunohistochemistry. RESULTS: Atorvastatin reduced the T-cell content, but did not change lipid, collagen, smooth muscle cell, or macrophage content. Plasma levels of apolipoprotein AI (apoAI) correlated positively with tissue collagen and inversely with metalloproteinase-9 and macrophage content. About half the specimens contained neutrophil granulocytes. CONCLUSIONS: Short-term atorvastatin treatment tended to reduce the T-cell content of atherosclerotic plaques, indicating modulation of cell-mediated immunity. High plasma levels of apoAI correlated with increased collagen content and reduced inflammation, supporting the notion that plasma apoAI stabilizes atherosclerotic plaques. The significance of neutrophils in the lesions merits further study.
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