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- Dollery, Clare M., et al.
(författare)
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Neutrophil elastase in human atherosclerotic plaques : production by macrophages
- 2003
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 107:22, s. 2829-2836
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease. Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheroma-related cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity.METHODS AND RESULTS: Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (n=7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1beta, TNF-alpha, or IFN-gamma but released it when stimulated by CD40 ligand, a cytokine found in atheroma.CONCLUSIONS: These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.
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| 2. |
- Jaiswal, Siddhartha, et al.
(författare)
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Clonal Hematopoiesis and risk of atherosclerotic cardiovascular disease
- 2017
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 377:2, s. 111-121
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. METHODS We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. RESULTS In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. CONCLUSIONS The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.)
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| 3. |
- Krettek, Alexandra, 1968-, et al.
(författare)
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Elastogenesis in human arterial disease : A role for macrophages in disordered elastin synthesis
- 2003
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 23:4, s. 582-587
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Elastin, an extracellular matrix protein, constitutes about 30% of the dry weight of the arteries. Elastolysis induced by inflammatory processes is active in chronic arterial diseases. However, elastogenesis in arterial diseases has received little attention. In this work we hypothesized that disordered elastogenesis is active in matrix remodeling in atheroma and abdominal aortic aneurysm (AAA).METHODS AND RESULTS: Human AAA and atheroma have 4- to 6-fold more tropoelastin protein than nondiseased arteries. The smooth muscle cell-containing media and fibrous cap of atherosclerotic arteries contain ordered mature elastin, whereas macrophage (MPhi)-rich regions often have disorganized elastic fibers. Surprisingly, in addition to smooth muscle cells, MPhis in diseased arteries also produce the elastin precursor tropoelastin, as shown by double immunostaining, in situ hybridization, and reverse transcription-polymerase chain reaction for tropoelastin mRNA. Cultured monocyte-derived MPhis can express the elastin gene. AAA have 9-fold but atheroma only 1.6-fold lower levels of desmosine, a marker for mature cross-linked elastin, than normal arteries.CONCLUSIONS: This study demonstrates ongoing but often ineffective elastogenesis in arterial disease and establishes human macrophages as a novel source for this important matrix protein. These results have considerable import for understanding mechanisms of extracellular matrix remodeling in arterial diseases.
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| 4. |
- Krettek, Alexandra, 1968-, et al.
(författare)
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Enhanced expression of CD44 variants in human atheroma and abdominal aortic aneurysm : possible role for a feedback loop in endothelial cells
- 2004
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Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 165:5, s. 1571-1581
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Tidskriftsartikel (refereegranskat)abstract
- CD44, a polymorphic hyaluronate receptor, may participate in chronic inflammation. We hypothesized that CD44 variants contribute to the development of arterial diseases. CD44 levels vary in normal and diseased arterial tissues in the following order: unaffected arteries < fibrous plaques < or = abdominal aortic aneurysm < atheromatous plaques; and correlate with macrophage content. Furthermore, plaque microvessels express CD44, and anti-CD44v3 or anti-CD44v6 treatment reduces endothelial cell proliferation but not apoptosis in vitro, suggesting functionality of these receptors. Endothelial cells express CD44H and CD44v6 after exposure to interleukin-1beta and tumor necrosis factor-alpha. Macrophages, a major source of abundant CD44 in vitro, express not only CD44H but also variants CD44v4/5, CD44v6, and CD44v7/8, isoforms distinctively regulated by proinflammatory cytokines. Several proinflammatory cytokines induce shedding of CD44 from the surface of macrophages and endothelial cells. Soluble CD44 stimulates the expression and release of interleukin-1beta from endothelial cells, suggesting a positive feedback loop of this cytokine. By demonstrating augmented expression of CD44 and variants within human atheroma and in abdominal aortic aneurysm as well as the vascular cell release of sCD44, a process regulated by proinflammatory cytokines, this study provides new insights on the functions of CD44 in arterial diseases.
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| 5. |
- Shi, Guo-Ping, et al.
(författare)
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Cystatin C deficiency in human atherosclerosis and aortic aneurysms
- 1999
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 104:9, s. 1191-1197
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C is normally expressed in vascular wall smooth muscle cells (SMCs), this cysteine protease inhibitor is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Furthermore, increased abdominal aortic diameter among 122 patients screened by ultrasonography correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-beta(1). The findings highlight a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and establish that cystatin C deficiency occurs in vascular disease.
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| 6. |
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| 7. |
- Yu, Weifang, et al.
(författare)
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Cystatin C Deficiency Promotes Epidermal Dysplasia in K14-HPV16 Transgenic Mice
- 2010
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cysteine protease cathepsins are important in extracellular matrix protein degradation, cell apoptosis, and angiogenesis. Mice lacking cathepsins are protected from tumor progression in several animal models, suggesting that the regulation of cathepsin activities controls the growth of various malignant tumors. Methods and Results: We tested the role of cathepsins using a mouse model of multistage epithelial carcinogenesis, in which the human keratin-14 promoter/enhancer drove the expression of human papillomavirus type 16 (HPV16) early region E6/E7 transgenes. During the progression of premalignant dysplasia, we observed increased expression of cysteine protease cathepsin S, but concomitantly reduced expression of cathepsin endogenous inhibitor cystatin C in the skin tissue extract. Absence of cystatin C in these transgenic mice resulted in more progression of dysplasia to carcinoma in situ on the face, ear, chest, and tail. Chest and ear skin extract real time PCR and immunoblot analysis, mouse serum sample ELISA, tissue immunohistological analysis, and tissue extract-mediated in vitro elastinolysis and collagenolysis assays demonstrated that cystatin C deficiency significantly increased cathepsin expression and activity. In skin from both the chest and ear, we found that the absence of cystatin C reduced epithelial cell apoptosis but increased proliferation. From the same tissue preparations, we detected significantly higher levels of pro-angiogenic laminin 5-derived c2 peptides and concurrently increased neovascularization in cystatin C-deficient mice, compared to those from wild-type control mice. Conclusion: Enhanced cathepsin expression and activity in cystatin C-deficient mice contributed to the progression of dysplasia by altering premalignant tissue epithelial proliferation, apoptosis, and neovascularization.
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