| 1. |
- Bartels, E. D., et al.
(author)
-
Endothelial lipase is highly expressed in macrophages in advanced human atherosclerotic lesions
- 2007
-
In: Atherosclerosis. - 0021-9150.
-
Journal article (peer-reviewed)abstract
- Endothelial lipase (EL) is expressed in endothelial cells, and affects plasma lipoprotein metabolism by hydrolyzing phospholipids in HDL. To determine the cellular expression of EL mRNA and protein in human atherosclerotic lesions, we performed in situ hybridization and immunohistochemical studies on sections of carotid endarterectomy specimens from patients with symptomatic cerebrovascular disease. In each of eight patients, EL mRNA and/or protein were seen in areas between the necrotic core and the fibrotic cap where they colocalized with LPL and macrophage-specific CD68. Moreover, there was a positive association between the expression of EL mRNA and CD68 mRNA in plaques from 26 patients. The impact of differentiation from monocytes into macrophages, and subsequently foam cells (by incubation with acetylated LDL) on expression was studied using THP-1 monocytes and primary human monocytes. EL mRNA expression increased markedly when either type of monocytes was differentiated into macrophages. Upon further differentiation into foam cells EL mRNA decreased whereas protein levels remained high compared to monocytes. In conclusion, macrophages in advanced human atherosclerotic lesions display high levels of EL expression, and the level of EL expression varies greatly during transformation of blood monocytes into foam cells.
|
|
| 2. |
- Behre, Carl Johan, 1968, et al.
(author)
-
The reciprocal association of adipocytokines with insulin resistance and C-reactive protein in clinically healthy men
- 2005
-
In: Metabolism. - 0026-0495. ; 54:4, s. 439-44
-
Journal article (peer-reviewed)abstract
- In experimental models, adiponectin improves and tumor necrosis factor alpha (TNF- alpha ) impairs insulin action, and the expression of these adipocytokines seems to have a reciprocal regulation. The aim was to examine whether in a cross-sectional study, associations supporting this concept may be found in 58-year-old clinically healthy men, and also the relation to C-reactive protein (CRP). In 102 men, euglycemic hyperinsulinemic clamp was used to assess glucose infusion rate (GIR). Total body fat (dual-energy x-ray absorptiometry), plasma adiponectin (radioimmunoassay), TNF-alpha , and CRP (enzyme-linked immunosorbent assay) were measured. Adiponectin correlated positively to GIR (r=0.33, P<.001) and negatively to total fat mass (r=-0.29, P=.004), whereas TNF- alpha showed reverse associations (r=-0.31, P<.01, and r=0.31, P<.01). Adiponectin and TNF- alpha were negatively correlated (-0.28, P=.006). An interaction term (TNF- alpha /adiponectin ratio) and body fat together explained 31.3% (P<.001) in GIR variability. The odds ratio for having insulin resistance was 9.3 (95% CI, 2.2-38.9) in subjects with TNF-alpha values above and adiponectin levels below the median, as compared to subjects with TNF- alpha values below and adiponectin levels above the median. Total fat and TNF-alpha , but not adiponectin, were significantly associated with log CRP (R2=20%, P<.001). In conclusion, this study in man showed that plasma adiponectin and TNF-alpha were independently and reversely associated with insulin resistance. C-reactive protein levels were related to TNF-alpha and obesity.
|
|
| 3. |
- Boström, Pontus, 1982, et al.
(author)
-
Hypoxia converts human macrophages into triglyceride-loaded foam cells.
- 2006
-
In: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636. ; 26:8, s. 1871-6
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Atherosclerotic lesions have regions that are hypoxic. Because the lesion contains macrophages that are loaded with lipid, we investigated whether hypoxia can influence the accumulation of lipids in these cells. METHODS AND RESULTS: Exposure of human macrophages to hypoxia for 24 hours resulted in an increased formation of cytosolic lipid droplets and an increased accumulation of triglycerides. Exposure of the macrophages to oxidized low-density lipoprotein (oxLDL) increased the accumulation of cytosolic lipid droplets because of an increase in cellular cholesterol esters. The accumulation of lipid droplets in oxLDL-treated cells was further increased after hypoxia, caused by an increased level of triglycerides. Expression analyses combined with immunoblot or RT-PCR demonstrated that hypoxia increased the expression of several genes that could promote the accumulation of lipid droplets. Hypoxia increased the mRNA and protein levels of adipocyte differentiation-related protein (ADRP). It is well known that an increased expression of ADRP increases the formation of lipid droplets. Hypoxia decreased the expression of enzymes involved in beta-oxidation (acyl-coenzyme A synthetase and acyl-coenzyme A dehydrogenase) and increased the expression of stearoyl-coenzyme A desaturase, an important enzyme in the fatty acid biosynthesis. Moreover, exposure to hypoxia decreased the rate of beta-oxidation, whereas the accumulation of triglycerides increased. CONCLUSIONS: The results demonstrate that exposure of human macrophages to hypoxia causes an accumulation of triglyceride-containing cytosolic lipid droplets. This indicates that the hypoxia present in atherosclerotic lesions can contribute to the formation of the lipid-loaded macrophages that characterize the lesion and to the accumulation of triglycerides in such lesions.
|
|
| 4. |
- Danielsson Norén, Kristina, et al.
(author)
-
15-Lipoxygenase-2 expression in human macrophages induces chemokine secretion and T cell migration.
- 2008
-
In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 199:1, s. 34-40
-
Journal article (peer-reviewed)abstract
- BACKGROUND: We determined previously that hypoxia results in increased 15-lipoxygenase type 2 (15-LOX-2) expression and CXCL8 secretion in macrophages. This study sought to determine whether 15-LOX-2 expression links directly with the secretion of inflammatory molecules in macrophages and also investigated its subsequent effects on T cell migration. METHODS: Adenovirus-mediated gene delivery caused overexpression of 15-LOX-2 in human macrophages. We used cytometric bead array to measure chemokine secretion, and assessed T cell migration by counting cells in chemotaxis chambers. Expression of chemokine receptors was determined by FACS analysis. Using siRNA, we reduced 15-LOX-2 expression in human macrophages. We used scrambled siRNA as control. RESULTS: Macrophages that overexpress 15-LOX-2 showed increased secretion of chemokine CXCL10 after 24h incubation. In addition, preconditioned medium from 15-LOX-2-overexpressing cells increased T cell migration and surface expression of CXCR3, the CXCL10 receptor. Knockdown of 15-LOX-2 expression decreased CXCL10 secretion from hypoxic macrophages and also reduced T cell migration. CONCLUSION: In macrophages, overexpression of 15-LOX-2 results in increased secretion of CXCL10 and CCL2. Products released in response to increased 15-LOX-2 activation lead to increased expression of CD69, the T cell activation marker as well as increased T cell migration. Therefore, increased expression of 15-LOX-2 induced by hypoxia may participate in T cell recruitment in diseases such as atherosclerosis.
|
|
| 5. |
- Fagerberg, Björn, 1943, et al.
(author)
-
C-reactive protein and tumor necrosis factor-alpha in relation to insulin-mediated glucose uptake, smoking and atherosclerosis.
- 2008
-
In: Scandinavian journal of clinical and laboratory investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; , s. 1-8
-
Journal article (peer-reviewed)abstract
- Objectives . To examine the hypothesis that serum concentration of C-reactive protein (CRP) is inversely associated with insulin sensitivity and obesity, and that this may by mediated by tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6). Material and methods . Cross-sectional, one-center study of a population-based sample of 58-year-old Swedish men (n = 98). Exclusion criteria were cardiovascular disease, clinical diabetes mellitus and/or continuous cardiovascular medication. Glucose infusion-rate (euglycemic hyperinsulinemic clamp), adjusted for fat-free mass, which together with total body fat was measured by dual-energy X-ray absorptiometry. Serum concentrations of CRP, TNFalpha, soluble TNFalpha receptor 2 (sTNFAR2), IL-6 determined by ELISA. Ultrasound was used to measure intima-media thickness (IMT) in both common carotid arteries, carotid bulbs and in the right femoral artery. Results . CRP was inversely associated with insulin sensitivity (r = -0.28, p<0.01) and with total body fat (r = 0.31, p<0.01), but not independently of the TNFalpha and sTNFAR2 product. Serum CRP, TNFalpha, sTNFAR2, but not IL-6, were associated with low insulin sensitivity, total body fat, abdominal obesity, hyperinsulinemia, hypertriglyceridemia, low HDL cholesterol and small LDL particles, i.e. the metabolic syndrome. These associations were independent of smoking and carotid and femoral artery IMT. Conclusions . Serum concentrations of CRP were related to insulin sensitivity and accompanying factors constituting the metabolic syndrome. The results indicate that this association may be mediated by adipose tissue and TNFalpha effects, the latter measured as the product of TNFalpha and sTNFAR2. This was a cross-sectional study and causality cannot be proven.
|
|
| 6. |
|
|
| 7. |
- Gunnarsson, Gudjon, et al.
(author)
-
Inhibitory effect of known antioxidants and of press juice from herring (Clupea harengus) light muscle on the generation of free radicals in human monocytes
- 2006
-
In: Journal of Agricultural and Food Chemistry. - : American Chemical Society (ACS). - 0021-8561 .- 1520-5118. ; 54:21, s. 8212-8221
-
Journal article (peer-reviewed)abstract
- Reactive oxygen species (ROS) can cause oxidative stress, which has been linked to various diseases. It has been suggested that antioxidant-rich foods can reduce such oxidative stress. However, the lack of suitable model systems to screen for in vivo effects of food-derived antioxidants has prevented a clear consensus in this area. In this study, the aim was to use a single-cell model system (human monocyte) to evaluate whether certain pure antioxidants and complex muscle extracts (herring light muscle press juice, PJ) could prevent ROS formation under in vivo like conditions. ROS were excreted from the monocytes upon stimulation with phorbol myristate acetate and were then detected as isoluminol-enhanced chemiluminescence (CL). Adding 2000 units of catalase and 50 units of superoxide dismutase to the monocytes model lowered the CL response by 35 and 86%, respectively. Ascorbate (14.1 mM) lowered the response by 99%, alpha-tocoperhol (188 microM) by 37%, and Trolox (50 microM) by almost 100%. Crude herring PJ gave a dose-dependent reduction in the CL response. At 10, 100, and 1000 times dilution, the PJ reduced the CL signal by 93, 60.5, and 10.6%. PJ fractionated into low molecular weight (LMW) (<1000 Da) and high molecular weight (>3500 Da) fractions decreased the CL response by 52.9 and 71.4%, respectively, at a 100-fold dilution. Evaluation of the PJ samples in the oxygen radical absorbance capacity test indicated that proteins may be the primary radical scavenging compounds of PJ, whereas the ROS-preventing effect obtained from the LMW fraction may also be attributed to other mechanisms. Thus, this study proved that the monocyte assay can be a useful tool for studying whether food-derived antioxidants can limit ROS production under physiologically relevant conditions. It also showed that herring contains numerous aqueous compounds demonstrating antioxidative effects in the monocyte model system.
|
|
| 8. |
- Hartford, Marianne, 1944, et al.
(author)
-
C-reactive protein, interleukin-6, secretory phospholipase A(2) group IIA and intercellular adhesion molecule-1 in the prediction of late outcome events after acute coronary syndromes
- 2007
-
In: J Intern Med. - : Wiley. - 0954-6820 .- 1365-2796. ; 262:5, s. 526-536
-
Journal article (peer-reviewed)abstract
- Objective. We investigated whether levels of C-reactive protein (CRP), interleukin-6 (IL-6), secretory phospholipase A(2) group IIA (sPLA(2)-IIA) and intercellular adhesion molecule-1 (ICAM-I) predict late outcomes in patients with acute coronary syndromes (ACS). Design. Prospective longitudinal study. CRP (mg L(-1)), IL-6 (pg mL(-1)), sPLA(2)-IIA (ng mL(-1)) and ICAM-1 (ng mL(-1)) were measured at days 1 (n = 757) and 4 (n = 533) after hospital admission for ACS. Their relations to mortality and rehospitalization for myocardial infarction (MI) and congestive heart failure (CHF) were determined. Setting. Coronary Care Unit at Sahlgrenska University Hospital, Gothenburg, Sweden. Subjects. Patients with ACS alive at day 30; median follow-up 75 months. Results. Survival was related to day 1 levels of all markers. After adjustment for confounders, CRP, IL-6 and ICAM-1, but not sPLA(2)-IIA, independently predicted mortality and rehospitalization for CHF. For CRP, the hazard ratio (HR) was 1.3 for mortality (95% confidence interval (CI): 1.1-1.5, P = 0.003) and 1.4 for CHF (95% CI: 1.1-1.9, P = 0.006). For IL-6, HR was 1.3 for mortality (95% CI: 1.1-1.6, P < 0.001) and 1.4 for CHF (95% CI: 1.1-1.8, P = 0.02). For ICAM-1, HR was 1.2 for mortality (95% CI: 1.0-1.4, P = 0.04) and 1.3 for CHF (95% CI: 1.0-1.7, P = 0.03). No marker predicted MI. Marker levels on day 4 provided no additional predictive value. Conclusions. In patients with ACS, CRP, IL-6, sPLA(2)-IIA and ICAM-1 are associated with long-term mortality and CHF, but not reinfarction. CRP, IL-6 and ICAM-1 provide prognostic information beyond that obtained by clinical variables.
|
|
| 9. |
- Hartford, Marianne, 1944, et al.
(author)
-
CRP, interleukin-6, secretory phospholipase A(2) group IIA, and intercellular adhesion molecule-1 during the early phase of acute coronary syndromes and long-term follow-up
- 2006
-
In: Int J Cardiol. - : Elsevier Ireland Ltd. ; 108:1, s. 55-62
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: The objectives of this study were to examine the time course of the inflammatory response in acute coronary syndromes (ACS) and to assess the markers of inflammation and their relation to disease severity. METHODS: We prospectively studied 134 patients with ACS who survived for at least 30 months. The patients were divided into four groups: acute myocardial infarction (MI) with (n=54) or without (n=46) ST-segment elevation and unstable angina with (n=14) or without (n=20) increased risk. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), secretory phospholipase A(2) group IIA (sPLA(2)-IIA), and intercellular adhesion molecule-1 (ICAM-1) were measured on days 1 and 4 and after 3 and 30 months. RESULTS: The highest levels of CRP and sPLA(2)-IIA were seen on day 4 but for IL-6 on day 1. These three markers, but not ICAM-1, were significantly related to disease severity, CKMB, and ejection fraction. Patients in Killip class II-IV had higher levels than those in Killip class I. The individual acute-phase responses correlated with marker levels at 3 and 30 months. ICAM-1 correlated with the development of congestive heart failure. CONCLUSIONS: In ACS there seems to be an individual predisposition to inflammatory response. Plasma IL-6 is the first marker to rise, while sPLA(2)-IIA and CRP peak later. All three markers, especially CRP, may discriminate between MI and non-MI. ICAM-1 seems to reflect other aspects of the inflammatory processes than the other markers. The results emphasize the complexity of the inflammatory response in ACS and stress the need for further studies involving multiple markers.
|
|
| 10. |
- Hiukka, A, et al.
(author)
-
ApoCIII-Enriched LDL in Type 2 Diabetes Displays Altered Lipid Composition, Increased Susceptibility for Sphingomyelinase and Increased binding to Biglycan.
- 2009
-
In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:9, s. 2018-2026
-
Journal article (peer-reviewed)abstract
- Objective- Apolipoprotein CIII (apoCIII) is an independent risk factor for cardiovascular disease, but the molecular mechanisms involved are poorly understood. Here, we investigated potential proatherogenic properties of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes. Research design and methods - LDL was isolated from controls and subjects with type 2 diabetes, and from apoB transgenic mice. LDL-biglycan binding was analyzed with a solid-phase assay using immunoplates coated with biglycan. Lipid composition was analyzed with mass spectrometry. Hydrolysis of LDL by sphingomyelinase was analyzed after labeling plasma LDL with [(3)H]sphingomyelin. ApoCIII isoforms were quantified after isoelectric focusing. Human aortic endothelial cells were incubated with desialylated apoCIII or with LDL enriched with specific apoCIII isoforms. Results- We showed that enriching LDL with apoCIII only induced a small increase in LDL-proteoglycan binding, and this effect was dependent on a functional Site A in apoB100. Our findings indicated that intrinsic characteristics of the diabetic LDL other than apoCIII per se are responsible for further increased proteoglycan binding of diabetic LDL with high endogenous apoCIII, and we showed alterations in the lipid composition of diabetic LDL with high apoCIII. We also demonstrated that high apoCIII increased susceptibility of LDL to hydrolysis and aggregation by SMase. In addition, we demonstrated that sialylation of apoCIII increased with increasing apoCIII content, and that sialylation of apoCIII was essential for its proinflammatory properties. Conclusions- We have demonstrated a number of features of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes that could explain the proatherogenic role of apoCIII.
|
|
