Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions

Weber, Christian; Erl, Wolfgang; Weber, Kim S.C.; Weber, Peter

doi:10.1515/cclm.1999.043

Cited by 48 publications

(24 citation statements)

References 87 publications

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“…The inhibitory effects of statins on interaction between ECs and PBMCs as shown in adhesion assay are consistent with the previous findings of Weber et al 34 These results suggest that the mechanisms by which statins reduce monocyte adhesion involve, at least in part, the downregulation of integrin expression in HUVECs.…”

Section: Discussionsupporting

confidence: 91%

Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients

Rezaie-Majd

Prager

Bucek

et al. 2003

ATVB

137

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Objective-The intercellular adhesion molecule-1 (ICAM-1/CD54) and its ligand, CD11a/CD18, mediate endothelial adhesion of leukocytes and their consecutive transmigration. Anti-inflammatory effects of statins are considered to be exerted in part through inhibition of leukocyte-endothelial interactions. We investigated the in vivo effects of simvastatin treatment in hypercholesterolemic patients and the influence of various statins on expression of cellular adhesion molecules in vitro. Methods and Results-A total number of 107 hypercholesterolemic patients were treated with 20 mg (nϭ52) or 40 mg (nϭ55) of simvastatin daily. After 6 weeks of treatment, peripheral blood mononuclear cells (PBMCs) expressed lower amounts of CD54-, CD18-, and CD11a-mRNA compared with pretreatment values. Surface expression of CD54 and CD18/CD11a on CD14 ϩ -monocytes also decreased significantly in both groups of patients. Moreover, simvastatin, atorvastatin, and cerivastatin were found to downregulate tumor necrosis factor (TNF)-␣-induced expression of CD54 and CD18/CD11a in isolated PBMCs obtained from normal donors as well as TNF-␣-dependent expression of these CAMs in cultured human umbilical vein endothelial cells (HUVECs). Furthermore, all three statins were found to reduce the binding of PBMCs to TNF-␣-stimulated HUVECs in vitro.

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Section: Discussionsupporting

confidence: 91%

Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients

Rezaie-Majd

Prager

Bucek

et al. 2003

ATVB

137

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“…Inhibitors of HMG CoA reductase (a key enzyme of cholesterol synthesis) such as lovastatin interfere with the expression of Mac-1 integrin and block the adhesive function of LFA-1 by direct binding to the I-domain. 154,155 Novel nonpeptide compounds have also been identi®ed for their ability to block ICAM-1/LFA-1 interaction. Through screening a compound library and subsequent optimization of potent ICAM-1/LFA-1 inhibitors, p-arylthio cinnamides with IC 50 values around 35 nM were identi®ed.…”

Section: S T R U C T U R a L B A S I S O F L Fmentioning

confidence: 99%

Inhibition of LFA‐1/ICAM‐1 and VLA‐4/VCAM‐1 as a therapeutic approach to inflammation and autoimmune diseases

Yusuf‐Makagiansar

Anderson

Yakovleva

et al. 2002

Medicinal Research Reviews

358

286

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This review focuses on providing insights into the structural basis and clinical relevance of LFA-1 and VLA-4 inhibition by peptides and small molecules as adhesion-based therapeutic strategies for inflammation and autoimmune diseases. Interactions of cell adhesion molecules (CAM) play central roles in mediating immune and inflammatory responses. Leukocyte function-associated antigen (LFA-1, alpha(L)beta(2), and CD11a/CD18) and very late antigen (VLA-4, alpha(4)beta(1), and CD49d/CD29) are members of integrin-type CAM that are predominantly involved in leukocyte trafficking and extravasation. LFA-1 is exclusively expressed on leukocytes and interacts with its ligands ICAM-1, -2, and -3 to promote a variety of homotypic and heterotypic cell adhesion events required for normal and pathologic functions of the immune systems. VLA-4 is expressed mainly on lymphocyte, monocytes, and eosinophils, but is not found on neutrophils. VLA-4 interacts with its ligands VCAM-1 and fibronectin (FN) CS1 during chronic inflammatory diseases, such as rheumatoid arthritis, asthma, psoriasis, transplant-rejection, and allergy. Blockade of LFA-1 and VLA-4 interactions with their ligands is a potential target for immunosuppression. LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases. The therapeutic intervention of mostly mAb-based has been extensively studied. However, due to the challenging relative efficacy/safety ratio of mAb-based therapy application, especially in terms of systemic administration and immunogenic potential, strategic alternatives in the forms of peptide, peptide mimetic inhibitors, and small molecule non-peptide antagonists are being sought. Linear and cyclic peptides derived from the sequences of LFA-1, ICAM-1, ICAM-2, VCAM-1, and FN C1 have been shown to have inhibitory effects in vitro and in vivo. Finally, understanding the mechanism of LFA-1 and VLA-4 binding to their ligands has become a fundamental basis in developing therapeutic agents for inflammation and autoimmune diseases.

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“…[43][44][45][46] Despite evidence of the formation of LTB4 in atherosclerotic lesions, 47 to date there have been very few previous studies suggesting that products of 5-lipoxygenase play any role in atherogenesis. 48,49 Aiello et al 35 provide two additional and intriguing observations that suggest that LTB4 mediates leukocyte recruitment into atherosclerotic lesions by indirect mechanisms. First, they demonstrate that the LTB4 receptor antagonist inhibits the LTB4-induced upregulation of CD11b expression in circulating monocytes from the treated mice.…”

Section: See Page 443mentioning

confidence: 99%

“…CD11b is the ␤2 integrin component of the CD11/CD18 complex on monocytes that mediates binding to ICAM-1 as well as to fibrinogen and heparin. 49 It is currently unclear to what extent ICAM-1 contributes to lesion formation as targeted knockout of ICAM-1 in mice only has a modest effect on inhibiting lesion formation. 27 Furthermore, Kubo et al 50 have shown that bone marrow transplantation with CD11b-deficient cells does not inhibit lesion formation in LDLR Ϫ/Ϫ mice.…”

Section: See Page 443mentioning

confidence: 99%

Leukocyte Recruitment Into Developing Atherosclerotic Lesions

Rosenfeld

2002

ATVB

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A few years ago, I was asked to give a series of lectures to our second-year medical students on basic inflammatory mechanisms. I was taking the place of the late Russell Ross, who had given these lectures for many years. Among the teaching materials Russ had collected was a videotape generated from a 16-mm movie made in the 1940s. The movie showed leukocytes rolling, adhering, and migrating through capillaries in response to an inflammatory stimulus in a rabbit ear chamber. I used this videotape to illustrate the basic steps in a classical inflammatory response but also to introduce to the students the remarkable complexity of the molecular interactions underlying each step in leukocyte recruitment into inflamed tissues. We have come a long way in delineating the nature of these molecular interactions since the 1940s. We now use in vitro adhesion assays and microscopic techniques such as intravital microscopy, coupled with antibodies and receptor antagonists designed to specify which candidate adhesion molecules, counter receptors, and chemokines mediate leukocyte recruitment 1-7 These have provided a basic molecular paradigm for the rolling, activation, arrest, adhesion, and transmigration of leukocytes. L and P selectins appear to be primarily responsible for the initial capture of cells from the flowing blood, E and P selectins for mediating rolling, and ␤2 integrins, ICAM-1, and PECAM-1 for adhesion and transmigration. 8 -10 In addition, products of the arachidonate and complement cascades and chemokines, a large family of small peptides that activate leukocytes via binding to G protein-coupled receptors, also seem to play fundamental roles in the recruitment process. [11][12][13] See page 443Most of our current knowledge of the molecular mediators of leukocyte recruitment has been derived from adhesion assays and studies of the microvasculature. Determining whether the same molecules are involved in recruiting leukocytes into atherosclerotic lesions in the muscular arteries has been more problematic. There is extensive evidence that many of these molecules are expressed by cells in human and experimental atherosclerotic lesions 14 -23 and that expression of adhesion molecules such as VCAM-1 is temporally related to lesion initiation and progression in animal models. 22,24 Furthermore, studies of transgenic mice or mice with targeted mutations have provided some insights into which of these molecules play roles in the atherogenic process. In particular, these studies have so far shown that E and P selectins, ICAM-1, MCP-1, and its receptor CCR2, as well as the IL-8 receptor CXCR2, seem to mediate recruitment of leukocytes into atherosclerotic lesions in hyperlipidemic mice. [25][26][27][28][29][30][31][32][33][34] However, the in vivo studies have also clearly demonstrated the presence of redundant mechanisms, as in no case has there been a complete ablation of lesion development in the absence of any one of these molecules. A look at the increasing list of known chemokines and the lack of specificity wit...

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Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions

Cited by 48 publications

References 87 publications

Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients

Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients

Inhibition of LFA‐1/ICAM‐1 and VLA‐4/VCAM‐1 as a therapeutic approach to inflammation and autoimmune diseases

Leukocyte Recruitment Into Developing Atherosclerotic Lesions

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