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...

The atherogenic effects of low-density lipoprotein (LDL) may be mediated, in part, by its effect(s) on endothelial-derived nitric oxide (NO). To determine whether LDL can modulate NO production by changing NO synthase expression, we treated human saphenous vein endothelial cells with increasing concentrations of native or oxidized LDL (0-100 micrograms/ml) for various durations (0-72 h). Oxidized, but not native LDL caused a time-dependent decrease in steady-state NO synthase mRNA levels. This coincided with a maximal 56% decrease in NOS activity was determined by [3H]arginine to [3H]citrulline conversion. In the presence of actinomycin D, treatment with oxidized LDL reduced the half-life of NO synthase mRNA from 36 to 10 h. This decrease in NO synthase mRNA correlated with the degree of LDL oxidation and was attenuated by pretreatment with cycloheximide. Nuclear run-off studies showed a biphasic transcriptional pattern of NO synthase gene with an initial 25% decrease during the first 6 h followed by a maximal 2.2-fold increase over baseline during the subsequent 18 h. These results indicate that oxidized LDL regulates endothelial NOS expression through a combination of early transcriptional inhibition and post-transcriptional mRNA destabilization.

No abstract

Abstract. We explicitly determine the high-energy asymptotics for WeylTitchmarsh matrices associated with general Dirac-type operators on half-lines and on R. We also prove new local uniqueness results for Dirac-type operators in terms of exponentially small differences of Weyl-Titchmarsh matrices. As concrete applications of the asymptotic high-energy expansion we derive a trace formula for Dirac operators and use it to prove a Borg-type theorem.