HMG-CoA Reductase Inhibitors Reduce MMP-9 Secretion by Macrophages

Bellosta, Stefano; Via, D. P.; Canavesi, M.; Pfister, Pascal; Fumagalli, R.; Paoletti, Rodolfo; Bernini, Franco

doi:10.1161/01.atv.18.11.1671

Cited by 469 publications

(308 citation statements)

References 49 publications

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“…reduction of platelet aggregation (84), inhibition of smooth muscle cell proliferation and migration (85), upregulation of endothelial NO synthetase (86) and inhibition of metalloprotease secretion (87). Our findings may be crucial for clinical benefits of statins, and may represent a novel anti-inflammatory paradigm for the mechanisms of action by this class of drugs (88), which warrants further detailed investigation with respect to leukocyte biology.…”

Section: Statins Inhibit Monocyte Adhesiveness In Patients With Hypermentioning

confidence: 86%

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

Weber¹,

Erl²,

Weber³

et al. 1999

CCLM

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The integrin heterodimer CD11b/CD18 (␣M␤2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2␣ (8-epi-PGF2␣) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear-resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet ␣IIb␤3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac-1-mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro, indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs.

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Section: Statins Inhibit Monocyte Adhesiveness In Patients With Hypermentioning

confidence: 86%

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

Weber¹,

Erl²,

Weber³

et al. 1999

CCLM

View full text Add to dashboard Cite

show abstract

“…However, cardiovascular drugs may attenuate the cardiovascular response to stress and some of the most common drugs, e.g. statins and aspirin, have the potential to inhibit gene expression and release of MMP-9 (Bellosta et al 1998, Hua et al 2009). Thus, it would have been difficult to interpret whether a difference in stress-induced release of MMP-9 between medicated CAD patients and unmedicated controls represented the effect of CAD itself or the effect of medication.…”

Section: Limitationsmentioning

confidence: 99%

Stress-induced release of matrix metalloproteinase-9 in patients with coronary artery disease: The possible influence of cortisol

Lundberg

Jonsson

Stenmark

et al. 2016

Psychoneuroendocrinology

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Stress-induced release of matrix metalloproteinase-9 in patients with coronary artery disease: The possible influence of cortisol, Psychoneuroendocrinology, 2016. 73() AbstractStress and inflammation are both important risk factors for coronary artery disease (CAD). However, the susceptibility to stress-induced inflammation and its determinants have been little explored in patients with CAD. Here, our aim was to study the stress-induced inflammatory response, more precisely the early release of matrix metalloproteinase (MMP)-9, and its association with cortisol response in patients with CAD. Sixty-four patients underwent a standardized laboratory stress test.The stress-induced release of MMP-9 was closely associated with the release of other neutrophilassociated proteins, MMP-8 and myeloperoxidase (MPO). It also showed a large variation among patients, as did cortisol. Twenty minutes after stress, a negative association between changes in MMP-9 and cortisol was seen (p<0.01). In vitro, dexamethasone reduced the IL-8-mediated release of MMP-9 from neutrophils, indicating that glucocorticoids may exert rapid effects on neutrophil activation. Further characterization of patients revealed that stress-induced release of MMP-9 was related to leukocyte telomere shortening and increased ultrasound-assessed plaque occurrence in the carotid arteries, but not to other characteristics such as age, gender or psychological background factors. The susceptibility to stress-induced release of MMP-9 may thus have impact on disease phenotype. Stress tests can be useful to identify CAD patients in need of novel prevention and treatment strategies.

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“…For example, statins suppress the innate immune response in vitro by inhibiting neutrophil migration (2), oxidative stress (3), NF-B activation (4), proinflammatory mediator release (5,6), expression of matrix metalloproteinases (7)(8)(9), and by increasing expression of constitutive NO synthase (10), peroxisome proliferator-activated receptor (PPAR) 3 ␣ (11), PPAR␥ (4), and TGF␤1 (12). Statins also suppress the adaptive immune response by inhibiting IFN-␥-inducible MHC class II expression (13), decreasing expression of CD40/CD40L (14), and by direct blockade of LFA-1 (15).…”

mentioning

confidence: 99%

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

Morimoto

Janssen²,

Fessler³

et al. 2006

The Journal of Immunology

200

179

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Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.

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HMG-CoA Reductase Inhibitors Reduce MMP-9 Secretion by Macrophages

Cited by 469 publications

References 49 publications

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

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

Stress-induced release of matrix metalloproteinase-9 in patients with coronary artery disease: The possible influence of cortisol

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

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