| 1. |
- Danielsson Norén, Kristina, et al.
(författare)
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15-Lipoxygenase-2 expression in human macrophages induces chemokine secretion and T cell migration.
- 2008
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 199:1, s. 34-40
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Knutsen Rydberg, Ellen, 1969, et al.
(författare)
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Hypoxia increases LDL oxidation and expression of 15-lipoxygenase-2 in human macrophages
- 2004
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Ingår i: Arterioscler Thromb Vasc Biol. ; 24:11, s. 2040-2045
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Macrophage-mediated oxidation of low-density lipoprotein (LDL) by enzymes, such as the lipoxygenases, is considered of major importance for the formation of oxidized LDL during atherogenesis. Macrophages have been identified in hypoxic areas in atherosclerotic plaques. METHODS AND RESULTS: To investigate the role of hypoxia in macrophage-mediated LDL oxidation, we incubated human monocyte-derived macrophages with LDL under normoxic (21% O2) or hypoxic (0% O2) conditions. The results showed that hypoxic macrophages oxidized LDL to a significantly higher extent than normoxic cells. Interestingly, the mRNA and protein expression of 15-lipoxygenase-2 (15-LOX-2) as well as the activity of this enzyme are elevated in macrophages incubated at hypoxia. Both the unspliced 15-LOX-2 and the spliced variant 15-LOX-2sv-a are found in macrophages. In addition, 15-LOX-2 was identified in carotid plaques in some macrophage-rich areas but was only expressed at low levels in nondiseased arteries. CONCLUSIONS: In summary, these observations show for the first time that 15-LOX-2 is expressed in hypoxic macrophages and in atherosclerotic plaques and suggest that 15-LOX-2 may be one of the factors involved in macrophage-mediated LDL oxidation at hypoxia.
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| 3. |
- Lindén, Tomas, et al.
(författare)
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Serum lipids, lipoprotein(a) and apo(a) isoforms in patients with established coronary artery disease and their relation to disease and prognosis after coronary by-pass surgery.
- 1998
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Ingår i: Atherosclerosis. - : Elsevier Ireland Ltd. - 0021-9150 .- 1879-1484. ; 137:1, s. 175-86
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Tidskriftsartikel (refereegranskat)abstract
- Consecutive patients (n=964) undergoing coronary angiography were studied and compared with a random population sample regarding serum lipids and lipoproteins with focus on lipoprotein(a) (Lp[a]) levels and apo(a) isoforms. The patients were also followed for 5 years after the angiography, and the prognostic value of serum lipoproteins were analyzed. The patients were divided in two groups: Group 1 (n=814) consisted of patients with angina pectoris and at least one coronary artery with 50% stenosis and group 2 (n=150) patients with none of the coronary arteries significantly obstructed ( < 50%). As controls a random population sample was selected (n=197). Blood samples were collected before coronary angiography for determination of serum lipids, Lp(a) and isoforms of apo(a). When group 1 and group 2 patients were compared, group 1 was found to have higher serum cholesterol, triglycerides, apoB and Lp(a) as well as lower HDL and apoAI. When group 1 was compared with the random sample, after correction for age and sex, similar differences were observed, except that the difference in Lp(a) was not significant. The high Lp(a) levels among patients was found to be primarily due to the female patients, where the difference compared to both group 2 and controls was highly significant (P=0.007 and P=0.001, respectively). There was a significant difference in the apo(a) isoform distribution between group 1 patients and control subjects (P=0.0003), with a higher frequency of low molecular weight isoforms among patients. This was also significant for the male subgroup (P=0.001). Lp(a), LDL, total cholesterol, triglycerides. apoB, HDL and apoAI were significantly related to the number of major coronary arteries with > 50% stenosis. Mortality during follow-up was,in a univariate analysis, significantly correlated to several factors related to the degree of heart disease and to LDL (P=0.02) and apoB (P < 0.01). Increased mortality was, however, related to low levels of apoB and LDL. For cardiac mortality no significant correlation to lipoprotein variables were found. In conclusion established lipoprotein risk factors were more frequent among patient with angina pectoris and verified coronary stenosis. Furthermore high Lp(a) levels and a high frequency of low molecular weight isoforms of apo(a) were found in coronary patients. Higher Lp(a) levels were observed both for female and male patients, the differences were, however, significant only for the female patients. None of the lipoprotein variables could predict coronary death during the follow-up period.
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| 4. |
- Mattsson Hultén, Lillemor, 1951, et al.
(författare)
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Human macrophages limit oxidation products in low density lipoprotein
- 2005
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Ingår i: Lipids Health Dis. - : BioMed Central (BMC). - 1476-511X. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- This study tested the hypothesis that human macrophages have the ability to modify oxidation products in LDL and oxidized LDL (oxLDL) via a cellular antioxidant defence system. While many studies have focused on macrophage LDL oxidation in atherosclerosis development, less attention has been given to the cellular antioxidant capacity of these cells. Compared to cell-free controls (6.2 +/- 0.7 nmol/mg LDL), macrophages reduced TBARS to 4.42 +/- 0.4 nmol/mg LDL after 24 h incubation with LDL (P = 0.022). After 2 h incubation with oxLDL, TBARS were 3.69 +/- 0.5 nmol/mg LDL in cell-free media, and 2.48 +/- 0.9 nmol/mg LDL in the presence of macrophages (P = 0.034). A reduction of lipid peroxides in LDL (33.7 +/- 6.6 nmol/mg LDL) was found in the presence of cells after 24 h compared to cell-free incubation (105.0 +/- 14.1 nmol/mg LDL) (P = 0.005). The levels of lipid peroxides in oxLDL were 137.9 +/- 59.9 nmol/mg LDL and in cell-free media 242 +/- 60.0 nmol/mg LDL (P = 0.012). Similar results were obtained for hydrogen peroxide. Reactive oxygen species were detected in LDL, acetylated LDL, and oxLDL by isoluminol-enhanced chemiluminescence (CL). Interestingly, oxLDL alone gives a high CL signal. Macrophages reduced the CL response in oxLDL by 45% (P = 0.0016). The increased levels of glutathione in oxLDL-treated macrophages were accompanied by enhanced catalase and glutathione peroxidase activities. Our results suggest that macrophages respond to oxidative stress by endogenous antioxidant activity, which is sufficient to decrease reactive oxygen species both in LDL and oxLDL. This may suggest that the antioxidant activity is insufficient during atherosclerosis development. Thus, macrophages may play a dual role in atherogenesis, i.e. both by promoting and limiting LDL-oxidation.
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