Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases.

Abstract

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cellspecific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. Rupture of coronary atheroma precipitates most acute myocardial infarctions (1). These plaque ruptures occur predictably at sites of thinning of the lesion's fibrous cap, areas frequently associated with accumulations of monocyte-derived macrophages (2-4), an important cellular component of the atherosclerotic plaques (5-8). Under certain conditions, mononuclear phagocytes can produce enzymes of the matrix metalloproteinase (MMP) family that are capable of degrading components of the extracellular matrix (9, 10). Thus, monocyte-derived foam cells may be the sources of matrixdegrading activity that may contribute to lability of the fibrous cap (2). However, the macrophages present in atherosclerotic plaques differ from the mononuclear phagocytes previously studied in relation to MMP production (11). Notably (13) and likely reflect the functions of lesional macrophages more faithfully than foam cells produced in culture. MATERIALS AND METHODSReagents. Cell types were identified using anti-muscle actin monoclonal antibody HHF-35 (Enzo Diagnostics) and anti-rabbit macrophage monoclonal antibody RAM-11 (Dako). Sheep polyclonal antibodies raised against rabbit interstitial collagenase (or MMP-1) (17) and sheep polyclonal antibodies against human stromelysin (or MMP-3) cross-reacting with rabbit MMP-3 were generously provided by Constance Brinckerhoff (Darmouth Medical School, Hanover, NH). Affinity-purified donkey antimouse antibodies conjugated to fluorescein or anti-sheep antibodies conjugated to lissamine rhodamine were from Jackson ImmunoResearch. Phorbol 12-myristate 13-acetate (PMA) and Escherichia coli lipopolysaccharide (LPS) serotype 055:B5 were from Sigma.Lesion Induction. Ten New Zealand male rabbits (2-3 kg, body weight) were divided into two groups for convenience and handled identically during the two experiments. Aortic macrophages were obtained from rabbits treated to produce aortic lesions rich in macrophage-derived foam cells (13, 16) by using a modification of procedures as described (13,18,19). Rabbits consumed a diet supplemented with 0.5% cholesterol a...

Effect of cerivastatin sodium, a new inhibitor of HMG‐CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits

“…These results are similar to those of previous studies using mature WHHL rabbits which su ered from established atherosclerosis treated with pravastatin alone (Shiomi et al, 1995) and in combination with cholestyramine (Shiomi et al, 1990). Davies et al (1993) reported that unstable plaques had large lipid cores, and Galis et al (1995) reported that macrophages secreted matrixdegradation proteinases, and collagen ®bres might be degraded. Therefore, reduction of atheromatous cores in the lesions is considered favourable with respect to stabilization of the plaque.…”

Modulation of matrix gelatinases and metalloproteinase-activating process in acute kidney rejection

“…Previous studies have shown that infiltration of the graft by immune cells has generally occurred by day 5 after transplantation in rat models [ 151. Since neutrophils and macrophages are important producers of MMP-9 [12,26,271, the increase in proMMP-9 activity measured in the cortex and the medulla could thus be the result of immune cell infiltration. Active MMP-9 produced by neutrophils may be rapidly degraded by proteinases, under some circumstances, to limit further tissue damage [27].…”

Evidence for an Active Inflammatory Process in the Hibernating Human Myocardium

“…33 Activated mast cells may be involved in tissue repair through the release of a wide variety of performed and newly synthesized mediators, such as the potent fibrogenic protease tryptase and a number of growth factors including basic fibroblast growth factors, vascular endothelial growth factor, and transforming growth factor-␤. 34 Both macrophages and mast cells are capable of producing matrix metalloproteinases, 35,36 critical factors in extracellular matrix metabolism. Accumulation of extracellular matrix proteins adversely affects myocardial viscoelasticity, leading to diastolic and systolic dysfunction.…”