Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the predilection site of atheromatous rupture.

Background: Rupture in the shoulder region of a coronary atheroma is considered to be a sequel to local extracellular matrix degradation in this highly vulnerable site. Such degradation could be triggered by mast cells, which are filled with neutral proteases and are present in coronary atheromas. However, the distribution and phenotype of mast cells within coronary atheromas have not been studied.

Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase.

In inflamed tissue sites characterized by on-going matrix degradation, the matrix metalloproteinases are secreted as latent precursors which are capable of proteolysis only after extracellular activation. Such areas often contain locally increased numbers of mast cells capable of releasing complexes between heparin proteoglycans and fully active endopeptidases with either tryptic (tryptase) or both tryptic and chymotryptic (chymase) activity. We have examined the ability of purified human skin chymase to activate human interstitial procollagenase (matrix metalloproteinase-1) in the absence and presence of heparin, the physiologic associate of chymase.

Mast cells of two types differing in neutral protease composition in the human aortic intima. Demonstration of tryptase- and tryptase/chymase-containing mast cells in normal intimas, fatty streaks, and the shoulder region of atheromas.

Biochemical studies in vitro have demonstrated that stimulated mast cells induce macrophage foam cell formation through the synergistic action of mast cell granule neutral proteases and proteoglycans. To determine the presence and number of mast cells in human arterial intima, the site of atherogenesis, specimens of normal and atherosclerotic human aortic intima from 35 autopsies of persons ranging from 13 to 67 years old were stained with monoclonal antibodies against the two major proteases of mast cells, tryptase and chymase. All mast cells present were found to contain tryptase, and an average of 40% contained chymase as well.

Proteolysis and fusion of low density lipoprotein particles independently strengthen their binding to exocytosed mast cell granules.

Contact between low density lipoproteins (LDL) and exocytosed mast cell granules, the "granule remnants," leads to binding of LDL to the granule remnants via ionic interactions between the apolipoprotein B-100 (apoB-100) component of LDL and the heparin proteoglycan component of the granule remnants. Upon incubation at 37 degrees C, the heparin proteoglycan-bound apoB-100 is progressively proteolyzed by remnant chymase and carboxypeptidase A, which are also bound to the heparin proteoglycans. Thereupon, the LDL particles fuse, and their binding to the granule remnants strengthens, as defined by the decreased ability of NaCl to release LDL from the remnants.

Proteolytic degradation of low-density lipoprotein by lipoprotein(a) and by recombinant apo(a).

The plasma concentration of lipoprotein(a) (Lp(a)) is correlated with the risk of atherosclerosis, and both Lp(a) and LDL are present in atherosclerotic lesions. Lp(a) is similar in structure to LDL, its distinguishing feature from LDL being the presence of one additional glycoprotein, apo(a), that is linked to apoB-100. Upon incubation of 125I-LDL with isolated Lp(a), we found a dose and time-dependent increase in the proportion of TCA-soluble radioactive material, demonstrating degradation of LDL.

The mast cell--a potential link between inflammation and cellular cholesterol deposition in atherogenesis.

Mast cells are present in the arterial intima, the site of atherogenesis. In fatty streaks (the initial stage of atherogenesis) some of these cells are detected in the close vicinity of cholesterol-loaded macrophage foam cells. To ascertain whether mast cells could be involved in the formation of foam cells, a model system was developed in which isolated rat serosal mast cells were incubated with mouse peritoneal macrophages in a medium enriched with either low density lipoproteins (LDL) or high density lipoproteins (HDL3).

Deletion of exon 15 of the LDL receptor gene is associated with a mild form of familial hypercholesterolemia. FH-Espoo.

We describe a mutation of the low-density lipoprotein (LDL) receptor gene, designated familial hypercholesterolemia (FH)-Espoo, which deletes exon 15 of the LDL receptor gene. The mutant receptor is predicted to lack 57 amino acids, including 18 serine and threonine residues, which are the sites of the clustered O-linked sugars of the receptor. Studies on 10 carriers of this gene revealed that FH-Espoo is associated with an exceptionally mild form of FH.

A leukocyte integrin binding peptide from intercellular adhesion molecule-2 stimulates T cell adhesion and natural killer cell activity.

Adhesion is of pivotal importance for a number of leukocyte functions. Little is known about the binding between leukocyte integrins and the intercellular adhesion molecules (ICAMs). Normally integrins are nonadhesive, and require a stimulus to become active.

Metabolism of LDL in mast cells recovering from degranulation. Description of a novel intracellular pathway leading to proteolytic modification of the lipoprotein.

Rat serosal mast cells contain cytoplasmic secretory granules composed of a proteoglycan matrix in which histamine and neutral proteases are embedded. On stimulation, these granules are exocytosed, but some of them remain in the degranulation channels where on exposure to the extracellular fluid, they lose their histamine and a fraction of their proteoglycans. In vitro, such granule remnants efficiently bind low density lipoprotein (LDL) present in the incubation medium.

Insulin resistance in familial and nonfamilial hypercholesterolemia.

High levels of very low density lipoprotein triglycerides and low levels of high density lipoprotein cholesterol have been found to be associated with insulin resistance measured by the euglycemic clamp technique. In contrast, the association of isolated hypercholesterolemia with insulin resistance has not been systematically studied. Therefore, we performed two separate studies designed to investigate the degree of insulin resistance in familial hypercholesterolemia (FH) (study 1) and nonfamilial hypercholesterolemia (non-FH) (study 2).

Inhibition of copper-mediated oxidation of LDL by rat serosal mast cells. A novel cellular protective mechanism involving proteolysis of the substrate under oxidative stress.

Rat serosal mast cells, when stimulated to exocytose their cytoplasmic granules, effectively blocked the copper-mediated oxidation of low density lipoproteins (LDLs) in vitro. This effect depended on the proteolytic activity of the formed extracellular granule remnants, since specific inhibition of chymase, the neutral protease that they contain, blocked the protective effect of the mast cells. The mechanism of this chymase-mediated inhibition of LDL oxidation was found to be binding of the copper ions present in the incubation medium by peptides released from LDL on proteolytic degradation of their apolipoprotein B (apoB) component.

Philadelphia chromosome as the sole abnormality and p210 bcr-abl chimeric protein expression in an Epstein-Barr virus-transformed B cell line from a patient with chronic myeloid leukemia.

A 'B' cell line, originating from a patient with chronic myeloid leukemia and containing the Philadelphia chromosome, was established after Epstein-Barr virus transformation. The Philadelphia chromosome was the sole chromosomal abnormality in this line, designated as PhB1 cell line. In DNA hybridization studies we detected rearrangements in the bcr gene and in the immunoglobulin heavy chain joining region.

Mast cell-mediated inhibition of reverse cholesterol transport.

Net cholesterol efflux from cholesterol-loaded macrophages, i.e., foam cells, was induced by incubating the foam cells with high density lipoprotein3 (HDL3).

The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland.

A mutation of the LDL receptor gene very common among Finnish patients with heterozygous familial hypercholesterolemia (FH) was identified. This mutation, designated as FH-North Karelia, deletes seven nucleotides from exon 6 of the LDL receptor gene, causes a translational frameshift, and is predicted to result in a truncated receptor protein. Only minute quantities of mRNA corresponding to the deleted gene were detected.

Gemfibrozil also corrects dyslipidemia in postmenopausal women and smokers.

We compared the efficacy of three formulations and two dosage regimens of gemfibrozil in 322 dyslipidemic (non-high-density lipoprotein [HDL] cholesterol level, greater than or equal to 5.2 mmol/L [greater than or equal to 200 mg/dL]) middle-aged male and postmenopausal female patients in a 1-year open-label trial. Of the patients studied, 109 received the standard 1200-mg dose of gemfibrozil, ie, two 300-mg capsules twice daily; 107 received one 600-mg tablet twice daily; and 106 received a single dose of 900 mg of gemfibrozil in two 450-mg tablets in the evening.

Soluble heparin proteoglycans released from stimulated mast cells induce uptake of low density lipoproteins by macrophages via scavenger receptor-mediated phagocytosis.

Stimulation of rat serosal mast cells in vitro triggers exocytosis of secretory granules from their cytoplasm. Thereupon, the granules lose their perigranular membranes, and about 40% of the heparin proteoglycans and all of the chondroitin sulfate proteoglycans that they initially contained are released into the incubation medium. At physiologic ionic strength and calcium ion concentration, the solubilized heparin proteoglycans, but not the chondroitin sulfate proteoglycans, form insoluble complexes with the low density lipoproteins (LDL) present.

Modification of low density lipoproteins by secretory granules of rat serosal mast cells.

When low density lipoprotein (LDL) is incubated with granules isolated from rat serosal mast cells, a fraction of LDL is bound to the granule heparin proteoglycan. If incubation is continued at 37 degrees C, the bound LDL, but not the unbound LDL, is degraded by granule neutral proteases. In the early stage of incubation, all the granule-bound LDL can be released by 0.

Mast cell granule-mediated uptake of low density lipoproteins by macrophages: a novel carrier mechanism leading to the formation of foam cells.

Mast cells are present in the arterial intima, the site of atherogenesis. To gain insight into the possible role of mast cells in the formation of the cholesterol-loaded macrophage foam cells typical of both early and late atherosclerotic lesions, a model system was developed in which isolated rat serosal mast cells were incubated with mouse peritoneal macrophages in medium to which low-density lipoproteins (LDL) had been added. Stimulation of the mast cells was found to induce a 50-fold enhancement of LDL uptake by the macrophages, which concomitantly accumulated LDL-derived cholesterol.

Effect of a low-molecular-weight B cell growth factor on the proliferation of normal and neoplastic lymphocytes in lymphomas.

The usefulness of low-molecular-weight B-cell growth factor (LMW-BCGF) for routine cytogenetic study of B cell non-Hodgkin lymphomas (NHL) was evaluated. Eighteen B cell lymphoma specimens were cultured for 4 days in the presence or absence of LMW-BCGF. After culture, conventional cytogenetic analysis was carried out, and the Morphology Antibody Chromosomes (MAC) method was used to study the frequencies of mitotic cells in different lymphocyte subsets.

Atheroma formation: defective control in the intimal round-trip of cholesterol.

This article is based on the concluding remarks by the author at the Ninth Paavo Nurmi Symposium on 'Lipoproteins and the Pathobiology of the Arterial Intima'. . .

The metabolism of low density lipoproteins by rat serosal mast cells.

Rat serosal mast cells contain secretory granules composed of a heparin proteoglycan matrix in which neutral proteases are embedded. Stimulation of the mast cells leads to granule exocytosis and formation of two pools of granules located extracellularly, firstly, granules expelled into the 'free' extracellular space and ultimately phagocytosed by the scavenging cells in the vicinity of mast cells and, secondly, granules which remain associated with their parent mast cells, and become internalized by them during recovery from stimulation. If mast cells are stimulated in the presence of macrophages in a low density lipoprotein (LDL)-containing medium, LDL is bound to the heparin proteoglycan component of the exocytosed granules whether they are expelled into the 'free' extracellular space or remain associated with the mast cells.