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| 43. |
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| 44. |
- Ljungberg, Liza, 1980-, et al.
(author)
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Global Transcriptional Profiling Reveals Novel Autocrine Functions of Interleukin 6 in Human Vascular Endothelial Cells
- 2020
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In: Mediators of Inflammation. - : Hindawi Publishing Corporation. - 0962-9351 .- 1466-1861. ; 2020
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Journal article (peer-reviewed)abstract
- Background: Interleukin 6 (IL6) is a multifunctional cytokine produced by various cells, including vascular endothelial cells. IL6 has both pro- and non-/anti-inflammatory functions, and the response to IL6 is dependent on whether it acts via the membrane-bound IL6 receptor alpha (IL6R alpha) (classic signaling) or the soluble form of the receptor (transsignaling). As human endothelial cells produce IL6 and at the same time express IL6R alpha, we hypothesized that IL6 may have autocrine functions.Methods: Knockdown of IL6 in cultured human endothelial cells was performed using siRNA. Knockdown efficiency was evaluated using ELISA. RNA sequencing was employed to characterize the transcriptional consequence of IL6 knockdown, and Ingenuity Pathway Analysis was used to further explore the functional roles of IL6.Results: Knockdown of IL6 in cultured endothelial cells resulted in a 84-92% reduction in the release of IL6. Knockdown of IL6 resulted in dramatic changes in transcriptional pattern; knockdown of IL6 in the absence of soluble IL6R alpha (sIL6R alpha) led to differential regulation of 1915 genes, and knockdown of IL6 in the presence of sIL6R alpha led to differential regulation of 1967 genes (fold change 1.5, false discovery rate<0.05). Pathway analysis revealed that the autocrine functions of IL6 in human endothelial cells are mainly related to basal cellular functions such as regulation of cell cycle, signaling, and cellular movement. Furthermore, we found that knockdown of IL6 activates functions related to adhesion, binding, and interaction of endothelial cells, which seem to be mediated mainly via STAT3.Conclusion: In this study, a large number of novel genes that are under autocrine regulation by IL6 in human endothelial cells were identified. Overall, our data indicate that IL6 acts in an autocrine manner to regulate basal cellular functions, such as cell cycle regulation, signaling, and cellular movement, and suggests that the autocrine functions of IL6 in human endothelial cells are mediated via IL6 classic signaling.
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| 45. |
- Loiske, Karin, 1978-
(author)
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Echocardiographic measurements of the heart : with focus on the right ventricle
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Echocardiography is a well established technique when evaluating the size and function of the heart. One of the most common ways to measure the size of the right ventricle (RV) is to measure the RV outflow tract 1(RVOT1). Several ways to measure RVOT1 are described in the literature.These ways were compared with echocardiography on 27 healthy subjects.The result showed significant differences in RVOT1, depending on the way it was measured, concluding that the same site, method and body positionshould be used when comparing RVOT1 in the same subject over time.One parameter to evaluate the RV diastolic function (RVDF) is to measure the RV isovolumetric relaxation time (RV-IVRT), a sensitive marker ofRV dysfunction. There are different ways to measure this. In this thesis two ways of measuring RV-IVRT and their time intervals were compared in 20 patients examined with echocardiography. There was a significant difference between the two methods indicating that they are not measuring the same interval.Another way to assess the RVDF is to measure the maximal early diastolicvelocity (MDV) in the long-axis direction. MDV can be measured bydifferent methods, hence 29 patients were examined and MDV was measured according to two methods. There was a good correlation but a poor agreement between the two methods meaning that reference values cannot be used interchangeably.Takotsubo cardiomyopathy is characterized by apical wall motion abnormalities without coronary stenosis. The pathology of this condition remains unclear. To evaluate biventricular changes in systolic long-axisfunction and diastolic parameters in the acute phase and after recovery, 13 patients were included and examined with echocardiography at admission and after recovery. The results showed significant biventricular improvementof systolic long-axis function while most diastolic parameters remainedunchanged.
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| 46. |
- Löntz, Werner, et al.
(author)
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Increased mRNA expression of manganese superoxide dismutase in psoriasis skin lesions and in cultured human keratinocytes exposed to IL-1 beta and TNF-alpha
- 1995
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In: Free Radical Biology & Medicine. - 0891-5849 .- 1873-4596. ; 18:2, s. 349-355
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Journal article (peer-reviewed)abstract
- Because reactive oxygen species have been implicated in the pathogenesis of various hyperproliferative and inflammatory diseases, the mRNA expression of the antioxidant enzyme superoxide dismutase was studied in psoriatic skin tissue. By using reverse transcription-PCR we found similar expression of copper, zinc superoxide dismutase (CuZnSOD) in the involved vs. uninvolved psoriatic skin. In contrast, the level of the manganese superoxide dismutase (MnSOD) mRNA message was consistently higher in lesional psoriatic skin as compared to adjacent uninvolved skin and healthy control skin. Parallel investigation of those cytokines that are thought to be direct or indirect inducers of the MnSOD activity revealed an increased mRNA expression of IL-1 beta, TNF-alpha, and GM-CSF in lesional psoriatic skin. To study if these cytokines exert a direct effect on dismutase expression in epidermal cells, human keratinocytes in culture were challenged with IL-1 beta, TNF-alpha, and GM-CSF. It was found that IL-1 beta and TNF-alpha, but not GM-CSF, induced the mRNA expression of MnSOD, and an additive effect was demonstrated for the two former cytokines. Further, the expression of both CuZnSOD and MnSOD transcripts was similar in cultured keratinocytes maintained at low differentiation (low Ca2+ medium) and cells forced to terminal differentiation (by high Ca2+ medium). Our results indicate that the abnormal expression of MnSOD mRNA in lesional psoriatic skin is not directly linked to the pathologic state of keratinocyte differentiation in the skin. It seems more likely that the cutaneous overexpression of MnSOD in psoriatic epidermis represents a protective cellular response evoked by cytokines released from inflammatory cells invading the diseased skin.
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| 47. |
- Nixon Tangi, Tebeng, et al.
(author)
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Role of NLRP3 and CARD8 in the regulation of TNF-α induced IL-1β release in vascular smooth muscle cells
- 2012
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In: International Journal of Molecular Medicine. - Athens, Greece : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 30:3, s. 697-702
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Journal article (peer-reviewed)abstract
- Interleukin (IL)-1β is known to be activated by the inflammasome. Inflammasome activities depend on a plethora of moieties including NLRP3 and CARD8, which have been reported to be associated with several inflammatory diseases. Aortic smooth muscle cells (AOSMCs) were transfected with siRNA targeting the NLRP3 and CARD8 genes, followed by tumor necrosis factor-α (TNF-α) treatment. We found that TNF-α induces IL-1β, IL-1Ra and NLRP3 genes but not CARD8. Silencing of the NLRP3 gene significantly decreased IL-1β expression and release, the IL-1Ra expression showed a borderline non-significant increment, while CARD8 knockdown did not affect the IL-1β and IL-1Ra mRNA expression or IL-1β protein release. Our results suggest that mainly NLRP3 plays a role in the regulation of IL-1β expression and release in AOSMC and could be a potential future target for the treatment of atherosclerosis and other inflammatory diseases.
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| 48. |
- Ocaya, Pauline Ajok, 1977-, et al.
(author)
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CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells
- 2011
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In: Journal of Vascular Research. - : S. Karger. - 1018-1172 .- 1423-0135. ; 48:1, s. 23-30
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Journal article (peer-reviewed)abstract
- Aim: The cytochrome P450 enzymes of the CYP26 family are involved in the catabolism of the biologically active retinoid all-trans-retinoic acid (atRA). Since it is possible that an increased local CYP26 activity would reduce the effects of retinoids in vascular injury, we investigated the role of CYP26 in the regulation of atRA levels in human aortic smooth muscle cells (AOSMCs).Methods: The expression of CYP26 was investigated in cultured AOSMCs using real-time PCR. The metabolism of atRA was analyzed by high-performance liquid chromatography, and the inhibitor R115866 or small interfering RNA (siRNA) was used to suppress CYP26 activity/expression.Results: AOSMCs expressed CYP26B1 constitutively and atRA exposure augmented CYP26B1 mRNA levels. Silencing of the CYP26B1 gene expression or reduction of CYP26B1 enzymatic activity by using siRNA or the inhibitor R115866, respectively, increased atRA-mediated signaling and resulted in decreased cell proliferation. The CYP26 inhibitor also induced expression of atRA-responsive genes. Therefore, atRA-induced CYP26 expression accelerated atRA inactivation in AOSMCs, giving rise to an atRA-CYP26 feedback loop. Inhibition of this loop with a CYP26 inhibitor increased retinoid signaling.Conclusion: The results suggest that CYP26 inhibitors may be a therapeutic alternative to exogenous retinoid administration. Copyright (C) 2010 S. Karger AG, Basel
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| 49. |
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| 50. |
- Ocaya, Pauline, et al.
(author)
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CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells
- 2007
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - Baltimore, Md : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 27:7, s. 1542-1548
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Intimal smooth muscle cells (SMCs) are dedifferentiated SMCs that have a powerful ability to proliferate and migrate. This cell-type is responsible for the development of intimal hyperplasia after vascular angioplasty. Retinoids, especially all-trans retinoid acid, are known to regulate many processes activated at sites of vascular injury, including modulation of SMC phenotype and inhibition of SMC proliferation. Intracellular levels of active retinoids are under firm control. A key enzyme is the all-trans retinoic acid-degrading enzyme cytochrome p450 isoform 26 (CYP26). Thus, an alternative approach to exogenous retinoid administration could be to increase the intracellular level of all-trans retinoic acid by blocking CYP26-mediated degradation of retinoids. METHODS AND RESULTS: Vascular intimal and medial SMCs expressed CYP26A1 and B1 mRNA. Although medial cells remained unaffected, treatment with the CYP26-inhibitor R115866 significantly increased cellular levels of all-trans retinoic acid in intimal SMCs. The increased levels of all-trans retinoic acid induced retinoid-regulated genes and decreased mitogenesis. CONCLUSIONS: Blocking of the CYP26-mediated catabolism mimics the effects of exogenously administrated active retinoids on intimal SMCs. Therefore, CYP26-inhibitors offer a potential new therapeutic approach to vascular proliferative disorders.
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