Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site

Weitz‐Schmidt, Gabriele; Welzenbach, Karl; Brinkmann, Volker; Kamata, Tetsji; Kallen, Joerg; Berthou, Christian; Cottens, Sylvain; Takada, Yoshikazu; Hommel, Ulrich

doi:10.1038/89058

Cited by 949 publications

(735 citation statements)

References 38 publications

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“…Soluble ICAM-1 has been shown to interact with the leukocyte ␤ 2 integrin (LFA-1), and it has been proposed as a useful marker of the inflammatory response (64). Closely related to this mechanism, statins have been shown to suppress the inflammatory response by binding directly to a regulatory site of the LFA-1 ␤ 2 integrin, which serves as a major counterreceptor for ICAM-1 on leukocytes (24).…”

Section: Discussionmentioning

confidence: 99%

“…Statins have also been shown to modify the function of ECs, smooth muscle cells, platelets, and monocytes/macrophages (22). Their effects include decreasing the expression of adhesion molecules in monocytes and leukocyte-endothelial interactions (23)(24)(25)(26), inhibiting platelet function (27), inhibiting tissue factor expression by mononuclear cells (28,29), down-regulating inflammatory cytokines in ECs (30), increasing fibrinolytic activity (31,32), and immunomodulation by decreasing the expression of class II major histocompatibility complex antigen (33).…”

Section: Conclusion These Findings Indicate That Fluvastatin Signifimentioning

confidence: 99%

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Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Ferrara¹,

Liu²,

Espinola³

et al. 2003

Arthritis & Rheumatism

138

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Methods. Two groups of CD-1 male mice, each comprising ϳ18 mice, were fed either normal saline solution or 15 mg/kg fluvastatin for 15 days. Each of the 2 groups was further subdivided to receive either purified IgG from patients with the antiphospholipid syndrome (IgG-APS) or normal IgG from healthy subjects. Analysis of thrombus dynamics was performed in treated and control mice, using a standardized thrombogenic injury procedure, and the area (size) of the thrombus was measured. Adhesion of leukocytes to ECs was analyzed with a microcirculation model of exposed cremaster muscle. Baseline and posttreatment soluble intercellular adhesion molecule 1 (sICAM-1) levels were determined by enzyme-linked immunosorbent assay.Results. IgG-APS mice treated with fluvastatin showed significantly smaller thrombi, a reduced number of adherent leukocytes, and decreased levels of sICAM-1 compared with IgG-APS animals treated with placebo.Conclusion. These findings indicate that fluvastatin significantly diminishes aPL-mediated thrombosis and EC activation in vivo. These results may have important implications for the design of new treatment strategies aimed at preventing recurrent thrombosis in patients with APS.

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Section: Discussionmentioning

confidence: 99%

Section: Conclusion These Findings Indicate That Fluvastatin Signifimentioning

confidence: 99%

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Ferrara¹,

Liu²,

Espinola³

et al. 2003

Arthritis & Rheumatism

138

View full text Add to dashboard Cite

show abstract

“…Statins prevent experimental T helper 1 (Th1)-mediated autoimmune diseases [95] and induce IL-4-dependent Th2-cell differentiation [96] and the secretion of antiinflammatory Th2-type cytokines [97]. Finally, statins can also bind to a novel allosteric site within the β 2 -integrin function-associated antigen-1 protein, independent of mevalonate production [98]. Inhibition of β 2 -integrin function-associated antigen-1 can decrease lymphocyte adhesion to ICAM-1 and impair T-cell co-stimulation [98].…”

Section: Statins and Agingmentioning

confidence: 99%

“…Finally, statins can also bind to a novel allosteric site within the β 2 -integrin function-associated antigen-1 protein, independent of mevalonate production [98]. Inhibition of β 2 -integrin function-associated antigen-1 can decrease lymphocyte adhesion to ICAM-1 and impair T-cell co-stimulation [98]. This is one of the few reported pleiotropic effects of statins that does not involve the inhibition of small GTPases.…”

Section: Statins and Agingmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

537

394

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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“…A novel way in which statins may regulate leukocyte-endothelial adhesion is by directly binding to a novel regulatory site, the L-site (named for lovastatin), on the integrin LFA-1 found on leukocytes (50). LFA-1, a ␤2 integrin, is critical in the development of inflammatory arthritis in the K/BxN serum transfer mouse model of arthritis.…”

Section: Statins As Antiinflammatory Drugs: Effects On Cells and Tissuesmentioning

confidence: 99%

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Abeles

Pillinger

2006

Arthritis & Rheumatism

136

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Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site

Cited by 949 publications

References 38 publications

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

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