| 51. |
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| 52. |
- Ovchinnikova, Olga, et al.
(författare)
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T-Cell Activation Leads to Reduced Collagen Maturation in Atherosclerotic Plaques of Apoe−/− Mice
- 2009
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Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 174:2, s. 693-700
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Tidskriftsartikel (refereegranskat)abstract
- Rupture of the collagenous, fibrous cap of an atherosclerotic plaque commonly causes thrombosis. Activated immune cells can secrete mediators that jeopardize the integrity of the fibrous cap. This study aimed to determine the relationship between T-cell-mediated inflammation and collagen turnover in a mouse model of experimental atherosclerosis. Both Apoe(-/-) x CD4dnT beta RII mice with defective transforming growth factor-beta receptors in T cells (and hence released from tonic suppression of T-cell activation) and lesion size-matched Apoe(-/-) mice were used. Picrosirius red staining showed a lower content of thick mature collagen fibers in lesions of Apoe(-/-) x CD4dnT beta RII mice, although both groups had similar levels of procollagen type I or M mRNA and total collagen content in lesions. Analysis of both gene expression and protein content showed a significant decrease of lysyl oxidase, the extracellular enzyme needed for collagen cross-linking, in aortas of Apoe(-/-) - CD4dnT beta RII mice. T-cell-driven inflammation provoked a selective and limited increase in the expression of proteinases that catabolize the extracellular matrix. Atheromata of Apoe(-/-) - CD4dnT beta RII mice had increased levels of matrix metalloproteinase-13 and cathepsin S mRNAs and of the active form of cathepsin S protein but no increase was detected in collagen fragmentation. our results suggest that exaggerated T-cell-driven inflammation limits collagen maturation in the atherosclerotic plaque while having little effect on collagen degradation.
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| 53. |
- Paloschi, Valentina, et al.
(författare)
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Impaired Splicing of Fibronectin Is Associated With Thoracic Aortic Aneurysm Formation in Patients With Bicuspid Aortic Valve
- 2011
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 31:3, s. 691-697
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients.METHODS AND RESULTS:The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (ρ=0.58) but not in BAV (ρ=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-β treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-β signaling pathway may explain the impaired EDA inclusion in BAV patients.CONCLUSIONS:Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.
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| 54. |
- Popov, Sergej, et al.
(författare)
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Salt-inducible kinase 1 influences Na+,K+-ATPase activity in vascular smooth muscle cells and associates with variations in blood pressure
- 2011
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Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 29:12, s. 2395-2403
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:Essential hypertension is a complex condition whose cause involves the interaction of multiple genetic and environmental factors such as salt intake. Salt-inducible kinase 1 (SIK1) is a sucrose-nonfermenting-like kinase isoform that belongs to the AMPK (5' adenosine monophosphate-activated protein kinase) family. SIK1 activity is increased by high salt intake and plays an essential role in regulating the plasma membrane Na(+),K(+)-ATPase. The objective of this study was to examine whether SIK1 is present in vascular smooth muscle cells (VSMCs) and endothelial cells, whether it affects VSMC Na(+),K(+)-ATPase activity and whether human SIK1 (hSIK1) represents a potential candidate for blood pressure regulation.METHODS:Localization of SIK1 was performed using immunohistochemistry, mRNA and western blot. Functional assays (Na(+),K(+)-ATPase activity) were performed in VSMCs derived from rat aorta. Genotype-phenotype association studies were performed in three Swedish and one Japanese population-based cohorts.RESULTS:SIK1 was localized in human VSMCs and endothelial cells, as well as a cell line derived from rat aorta. A nonsynonymous single nucleotide polymorphism in the hSIK1 gene exon 3 (C→T, rs3746951) results in the amino acid change (15)Gly→Ser in the SIK1 protein. SIK1-(15)Ser was found to increase plasma membrane Na(+),K(+)-ATPase activity in cultured VSMC line from rat aorta. Genotype-phenotype association studies in three Swedish and one Japanese population-based cohorts suggested that T allele (coding for (15)Ser) was associated with lower blood pressure (P = 0.005 for SBP and P = 0.002 for DBP) and with a decrease in left ventricular mass (P = 0.048).CONCLUSION:The hSIK1 appears to be of potential relevance within VSMC function and blood pressure regulation.
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| 55. |
- Rossignoli, Aranzazu, et al.
(författare)
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Plasma cholesterol lowering in an AngII-infused atherosclerotic mouse model with moderate hypercholesterolemia
- 2018
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 42:1, s. 471-478
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is the main underlying causes of cardiovascular disease. There is a well‑established association between high blood cholesterol levels and the extent of atherosclerosis. Furthermore, atherosclerosis has been proposed to augment abdominal aortic aneurysm (AAA) formation. As patients with AAA often have parallel atherosclerotic disease and are therefore often on cholesterol‑lowering therapy, it is not possible to fully address the independent effects of plasma cholesterol lowering (PCL) treatment on AAA. The present study investigated the effect of angiotensin II (AngII)‑infusion in modestly hypercholesterolemic Ldlr‑/‑Apob100/100Mttpflox/floxMx1‑Cre mice with or without PCL treatment on a morphological and molecular level, in terms of atherosclerosis and AAA development. AngII infusion in the study mice resulted in an increased atherosclerotic lesion area and increased infiltration of inflammatory leukocytes, which was not observed in mice with PCL induced prior to AngII infusion. This suggested that AngII infusion in this mouse model induced atherosclerosis development, and that plasma cholesterol levels represent a controlling factor. Furthermore, AngII infusion in Ldlr‑/‑Apob100/100Mttpflox/floxMx1‑Cre mice caused a modest aneurysmal phenotype, and no differences in AAA development were observed between the different study groups. However, the fact that modest hypercholesterolemic mice did not develop AAA in a classical aneurysmal model indicated that plasma cholesterol levels are important for disease development.
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| 56. |
- Rullman, E., et al.
(författare)
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A single bout of exercise activates matrix metalloproteinase in human skeletal muscle
- 2007
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 102:6, s. 2346-2351
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were 1) to characterize changes in matrix metalloproteinase (NIMP), endostatin, and vascular endothelial growth factor (VEGF)-A expression in skeletal muscle in response to a single bout of exercise in humans; and 2) to determine if any exchange of endostatin and VEGF-A between circulation and the exercising leg is associated with a change in the tissue expression or plasma concentration of these factors. Ten healthy males performed 65 min of cycle exercise, and muscle biopsies were obtained from the vastus lateralis muscle at rest and immediately and 120 min after exercise. In the muscle biopsies, measurements of mRNA expression levels of MMP-2, MMP-9, MMP-14, and tissue inhibitor of metalloproteinase; VEGF and endostatin protein levels; and NIMP activities were performed. Femoral arterial and venous concentrations of VEGF-A and endostatin were determined before, during, and 120 min after exercise. A single bout of exercise increased MMP-9 mRNA and activated MMP-9 protein in skeletal muscle. No measurable increase of endostatin was observed in the skeletal muscle or in plasma following exercise. A concurrent increase in skeletal muscle VEGF-A mRNA and protein levels was induced by exercise, with no signs of peripheral uptake from the circulation. However, a decrease in plasma VEGF-A concentration occurred following exercise. Thus 1) a single bout of exercise activated the MMP system without any resulting change in tissue endostatin protein levels, and 2) the increased VEGF-A protein levels are due to changes in the skeletal muscle tissue itself. Other mechanisms are responsible for the observed exercise-induced decrease in VEGF-A in plasma.
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| 57. |
- Rullman, E, et al.
(författare)
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Circulating MMP-9 during exercise in humans
- 2013
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Ingår i: European Journal of Applied Physiology. - : Springer Verlag (Germany). - 1439-6319 .- 1439-6327. ; 113:5, s. 1249-1255
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinase 9 (MMP-9) is a member of a family of zinc-dependent endopeptidases capable of degrading extracellular matrix (ECM) proteins. A single bout of exercise increases levels of activated MMP-9 in skeletal muscle and in the circulation. However, whether the exercise-induced activation of MMP-9 is associated with ECM remodeling and the cellular source behind MMP-9 in the circulation is not known. In the present study ten healthy male subjects performed a single cycle exercise bout and arterial and venous femoral blood was collected. To test if exercise induces basal lamina degradation and if circulating levels of MMP-9 is related to a release from the exercising muscle, arteriovenous differences of collagen IV and MMP-9 were measured by ELISA and zymography, respectively. Furthermore, markers of neutrophil degranulation elastase and neutrophil gelatinase-associated lipocalin (NGAL) were measured by ELISA. Plasma levels of collagen IV increased during the exercise bout and an increased arteriovenous difference of collagen IV was noted at 27 min of exercise. Plasma levels of MMP-9 were increased at both 27 and 57 min of exercise but no arteriovenous difference was noted. No changes over time were detected for elastase and NGAL. The observed release of collagen IV from the exercising muscle indicate basal lamina turnover following a single bout of exercise. No detectable release of MMP-9 was observed, suggesting that the increase in plasma MMP-9 could come from a source other than the skeletal muscle.
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| 58. |
- Rullman, Eric, et al.
(författare)
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Endurance exercise activates matrix metalloproteinases in human skeletal muscle
- 2009
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 106:3, s. 804-812
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, the effect of exercise training on the expression and activity of matrix metalloproteinases (MMPs) in the human skeletal muscle was investigated. Ten subjects exercised one leg for 45 min with restricted blood flow and then exercised the other leg at the same absolute workload with unrestricted blood flow. The exercises were conducted four times per week for 5 wk. Biopsies were taken from the vastus lateralis muscles of both legs at rest before the training period, after 10 days and 5 wk of training, and 2 h after the first exercise bout for analysis of MMP and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA, enzyme activity, and protein expression. Levels of MMP-2, MMP-14, and TIMP-1 mRNA in muscle tissue increased after 10 days of training regardless of blood flow condition. MMP-2 mRNA level in laser-dissected myofibers and MMP-2 activity in whole muscle increased with training. The level of MMP-9 mRNA and activity increased after the first bout of exercise. Although MMP-9 mRNA levels appeared to be very low, the activity of MMP-9 after a single bout of exercise was similar to that of MMP-2 after 10 days of exercise. MMP-2 and MMP-9 protein was both present throughout the extracellular matrix of the muscle, both around fibers and capillaries, but MMP-2 was also present within the skeletal muscle fibers. These results show that MMPs are activated in skeletal muscle in nonpathological conditions such as voluntary exercise. The expression and time pattern indicate differences between the MMPs in regards of production sites as well as in the regulating mechanism
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| 59. |
- Sevastianova, K, et al.
(författare)
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Comparison of Dorsocervical With Abdominal Subcutaneous Adipose Tissue in Patients With and Without Antiretroviral Therapy-Associated Lipodystrophy
- 2011
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 60:7, s. 1894-1900
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Combination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intra-abdominally. No fat is lost dorsocervically and it can even accumulate in this region (buffalo hump). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1-infected cART-treated patients with (cART+LD+) and without (cART+LD-) lipodystrophy. RESEARCH DESIGN AND METHODS: We used histology, microarray, PCR, and magnetic resonance imaging to compare dorsocervical and abdominal subcutaneous adipose tissue in cART+LD+ (n=21) and cART+LD- (n=11). RESULTS: Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA; copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD-. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical versus abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot. CONCLUSIONS: Because mtDNA is depleted even in the nonatrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal subcutaneous adipose tissue is in expression of homeobox genes.
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| 60. |
- Shamoun, Levar, et al.
(författare)
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Association of gene and protein expression and genetic polymorphism of CC chemokine ligand 4 in colorectal cancer
- 2021
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group. - 1007-9327 .- 2219-2840. ; 27:30, s. 5076-5087
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Leukocytes, such as T cells and macrophages, play an important role in tumorigenesis. CC chemokine ligand (CCL) 4, which is produced by lymphocytes and macrophages, has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes. AIM To examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer (CRC) and evaluate their prognostic significance. METHODS Luminex technology was used to determine CCL4 Levels in CRC tissue (n = 98), compared with paired normal tissue, and in plasma from patients with CRC (n = 103), compared with healthy controls (n = 97). Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery, Ryhov County Hospital, Jönköping, Sweden. Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue (n = 101). Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls. RESULTS The CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue (90%, P < 0.001 and 45%, P < 0.05, respectively). CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease. Low CCL4 protein expression levels in CRC tissue were associated with a 30% lower cancer-specific survival rate in patients (P < 0.01). The level of plasma CCL4 was 11% higher in CRC patients than in healthy controls (P < 0.05) and was positively correlated (r = 0.56, P < 0.01) with the CCL4 protein level in CRC tissue. The analysis of CCL4 gene polymorphism rs10491121 showed a difference (P < 0.05) between localized disease and disseminated disease in the right colon, with a dominance of allele A in localized disease. Moreover, the rate of the A allele was higher among CRC patients with mucinous cancer than among those with nonmucinous cancer. CONCLUSION The present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121, particularly in the right colon, are associated with clinical outcome in CRC patients.
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