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Biomedical subjects

A M Fogelman

Publications and source records attributed to A M Fogelman.

144 records · Page 8Linked to original sources
PubMed1977

Pathophysiology of myocardial infarction.

Primary prevention of death from ischemic heart disease requires further understanding of the pathogenesis of this disorder. Cellular defects of cholesterol metabolism may be more significant markers that serum lipid levels for the identification and treatment of atherosclerotic risk. Coronary spasm has been shown to be an important cause of ischemia in the presence and absence of atherosclerotic lesions. Careful manipulation of physiologic variables with vasodilator agents during cardiopulmonary bypass can substantially alter the myocardial oxygen supply-demand relation, thereby minimizing ischemic injury. The cellular basis for loss of mechanical function during ischemia and the factors that determine irreversible injury are yet unknown.

Action Potentials↗
PubMed1976

Mevalonate metabolism: role of kidneys.

More than one-half of the amount of mevalonate that is metabolized by pathways not leading to sterols is accounted for by the action of the kidneys. Conversion of mevalonate in vivo to squalene and sterols in the kidneys is confined almost entirely to the proximal and distal convoluted tubules in the cortex. More sterol than squalene is synthesized from mevalonate not only in the liver but also in the kidney.

Animals↗
PubMed1975

Abnormal induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase in leukocytes from subjects with heterozygous familial hypercholesterolemia.

Human leukocytes isolated from fresh defibinated blood were shown to utilize acetate and mevalonate for sterol synthesis. The capacity of the leukocytes to synthesize sterols is limited severely as compared to their ability to convert mevalonate into farnesyl pyrophosphate (which they hydrolyze rapidly to free farnesol) and into squalene. When leukocytes are incubated in a medium containing lipid-free serum, synthesis of sterols from acetate, but not from mevalonate, is much enhanced. It was shown that this increased synthesis resulted from increased levels of 3-hydroxy-3-methylglutaryl-CoA reductase activity in the cells. A comparison was made of the activation of sterol synthesis from acetate in leukocytes of normal individuals and of heterozygous familial hypercholesterolemics. The latter group responded to incubation in lipid-free sera with a significantly higher activation than the cells of normocholesterolemics. This activation was shown to be well correlated with a higher induction of 3-hydroxy-3-methylglutaryl-CoA reductase in the heterozygous cells than in the normals. The leukocytes of a heterozygous familial hypercholesterolemic individual were found to release, into a lipid-free incubation medium, more endogenously synthesized [3H]sterol (but not [3H]squalene) than the cells of a normal person. It is suggested that the genetic abnormality in heterozygous familial hypercholesterolemia could be accounted for by a mutation resulting in a weaker binding of a sterol repressor by heterozygous cells than by normal cells.

Acetates↗
PubMed1975

Metabolism of mevalonate in rats and man not leading to sterols.

C-5 of mevalonate appears as C0-2 in the breath of rats and men almost immediately after administration either by injection or by mouth. Adult rats exhaled up to 6.5% of a dose of RS-[5-14C]mevalonate (13% of the utilizable R-enantiomer) in the breath in 100 min. The 14-C02 was not derived either from the matabolism of cholesterol biosynthesized from [5-14C]mevalonate or from the metabolism of the unnatural S-enantiomer of mevalonate. The amount of 14-C02 expired in the breath was the same whether the [5-14C]mevalonate was given intravenously or in a drink of water to man. One normocholesterolemic man dissipated 12%, a mildly non-familial hypercholesterolemic man dissipated 10%, and a familial hypercholesterolemic man dissipated 7% of a dose of [5-14C]mevalonate in 24 hours (calculated as a per cent of the R-enantiomer). The observations support the hypothesis of the existence of a metabolic shunt of intermediates of sterol biosynthesis, derived from mevalonate, not leading to sterols.

Adult↗
PubMed1975

Echocardiographic evaluation of posterior left ventricular wall motion in muscular dystrophy.

Maximal systolic endocardial velocity (SEVM) and maximal diastolic endocardial velocity (DEVM) were determined echocardiographically in patients with muscular dystrophy (MD). The SEVM of the muscular dystrophy patients was 5.5 +/- 0.9 cm/sec and the DEVM was 13 +/- 3 cm/sec. The SEVM in MD was significantly less than that seen in age-matched normals (P less than 0.05), persons with myotonia congenita (P less than 0.02), deconditioned patients (P less than 0.001), or older normal persons (P less than 0.05). The Sevm of the MD patients was not significantly different from persons with spinal muscular atrophy. The DEVM of the muscular dystrophy patients was significantly less (P less than 0.001-0.05) than any other group. No correlation could be found between age, heart rate, type or severity of dystrophy and SEVM or DEVM values. The echocardiogram was more selective in correctly identigying muscular dystrophy patients than the electrocardiogram. The abnormality in DEVM was present despite lack of symptoms, normal cardiovascular examination, normal chest X-ray and normal electrocardiograms in 18 of 22 patients. We believe that the DEVM correlates with myocardial relaxation.

Adolescent↗
PubMedDate not supplied

The role of high-density lipoproteins in oxidation and inflammation.

High-density lipoproteins (HDL) in the basal state are anti-inflammatory, capable of destroying oxidized lipids that generate an inflammatory response. However, HDL during acute inflammation are altered and become pro-inflammatory. This "chameleon-like" nature of HDL is considered to be due to the complex composition of HDL. The data reviewed here demonstrate the key role of HDL in modulating inflammation and its implications for atherogenesis.

Animals↗
PubMedDate not supplied

Lipid accumulation in rabbit aortic intima 2 hours after bolus infusion of low density lipoprotein. A deep-etch and immunolocalization study of ultrarapidly frozen tissue.

The intima from aortas of normal New Zealand White rabbits was studied 2 hours after infusion of 320 mg human low density lipoprotein (LDL), resulting in a plasma concentration of at least five times and maximally 20 times the values found in normal rabbit serum. The following techniques were used: 1) ultrarapid freezing without chemical fixation, followed by freeze-etching; 2) immunofluorescence microscopy; and 3) postembedding immunogold-labeling electron microscopy. In the latter two methods MB47, a murine monoclonal antibody against human apolipoprotein B, was used as the primary antibody. Control rabbits were infused with the same volume of buffer only. Rotary-shadowed replicas of samples from the LDL-injected rabbits showed the deposition of lipidlike particles in the subendothelial-intimal space that were the size of the injected LDL (23 nm). In focal areas of the intima, groups of 23-nm-sized lipidlike particles and larger lipidlike structures were found enmeshed in the extracellular matrix. Control replicas were essentially free of lipid deposition. Immunofluorescence microscopy of frozen aortic cross sections showed an overall increase in apolipoprotein B in the intima of the LDL-injected rabbits. The presence of apolipoprotein B in the intima was also confirmed by immunoelectron microscopy. These in vivo results show that clustering of LDL-sized particles occurs in the intima within 2 hours of excessive LDL uptake. It also demonstrates the interaction of these LDL-sized particles with the filaments of the extracellular matrix. The clustering of the LDL-sized particles supports the possibility that LDL self-aggregation may occur in vivo and that components of the extracellular matrix are involved in this process.

Animals↗
PubMedDate not supplied

LDL, scavenger, and beta-VLDL receptors on aortic endothelial cells.

Primary and first passage aortic endothelial cells were shown to possess a high affinity receptor for beta-migrating very low density lipoproteins (beta-VLDL) distinct from the low density lipoprotein (LDL) receptor and scavenger receptor on these cells. In bovine aortic endothelial cells, 125I-rabbit beta-VLDL was taken up and degraded by a high affinity process that was competed for by unlabeled rabbit beta-VLDL and unlabeled postprandial VLDL from a fat-fed normal subject. However, unlabeled human or rabbit LDL, human LDL modified by malondialdehyde (MDA-LDL), or VLDL from a fasted normal human or a rabbit were not effective competitors for the degradation of 125I-rabbit beta-VLDL. In contrast to the receptor-mediated degradation of 125I-human or rabbit LDL and 125I-human-MDA-LDL, cell density did not affect the receptor-mediated degradation of 125I-rabbit beta-VLDL. Endothelial cells from a Watanabe heritable hyperlipidemic (WHHL) rabbit virtually did not degrade rabbit LDL, but degraded rabbit beta-VLDL at a rate equal to that seen in normal rabbit endothelial cells. It was concluded that the beta-VLDL receptor on endothelial cells is genetically distinct from the LDL receptor. Incubation of cells for 3 days with 100 micrograms/ml protein of unlabeled beta-VLDL caused an 88% increase in cellular cholesterol content, even though the beta-VLDL receptor activity was down-regulated by 60%. Endothelial cells and monocyte-macrophages are thus far the only cells known to possess the LDL receptor, the scavenger receptor, and the beta-VLDL receptor.

Acetates↗
PubMedDate not supplied

Monocyte chemotactic factor produced by large vessel endothelial cells in vitro.

Cultured rabbit aortic and human carotid artery endothelial cells produced a factor that was chemotactic for monocytes but not for neutrophils. Checkerboard analysis showed that the activity was due to chemotaxis and not to chemokinesis. The factor was produced in both serum-containing and serumless media. Treatment with carboxypeptidase and trypsin resulted in inhibition of chemotactic activity, indicating that the factor is a peptide. Medium from cultures of rabbit aortic, human carotid artery, and human umbilical vein endothelial cells previously exposed to beta migrating very low density lipoprotein (beta-VLDL) had substantially more chemotactic activity than medium from untreated cells or cells exposed to low density lipoprotein. beta-VLDL alone had no chemotactic activity. We conclude that large vessel endothelial cells produce a monocyte chemotactic factor that is increased after exposure of the cells to beta-VLDL.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMedDate not supplied

Beta-very low density lipoprotein pretreatment of endothelial monolayers increases monocyte adhesion.

Treatment of rabbit aortic endothelial cells or human umbilical vein cells for as little as 1 day with 25 micrograms/ml of beta-migrating very low density lipoprotein (beta-VLDL), but not low density lipoprotein (LDL), caused an increased binding of human peripheral blood monocytes to the endothelium. This increase was maximal by 24 hours but was not significant at 4 hours of pre-incubation with beta-VLDL. Neutrophil binding was not significantly stimulated by beta-VLDL treatment of endothelial cells, while endotoxin (LPS) treatment of endothelial cells stimulated both neutrophil and monocyte binding. Antibody to leukocyte function-associated-antigen-1 and to Mo2 inhibited binding to both beta-VLDL-stimulated and LPS-stimulated cells by 25%. The fact that both rabbit and human cells were stimulated by beta-VLDL to bind human monocytes suggests that some mechanisms regulating binding are conserved between species. These studies suggest that beta-VLDL acts like a chronic inflammatory mediator to cause a sustained increase in binding of monocytes to the endothelium.

Animals↗
PubMedDate not supplied

Antibodies to the T-cell receptor (CD3) induce LFA-1/Mac-1-dependent mononuclear cell adhesion to human arterial endothelium.

Monoclonal antibodies to the CD3 determinant on T lymphocytes have been used extensively as immunosuppressive agents. The T-cell receptor forms a complex with CD3 so that antibodies to CD3 mimic T-cell receptor cross-linking by human leukocyte antigens. Both CD3 and T-cell receptor cross-linking have been associated with lymphocyte activation and expression of the LFA-1 adhesion ligand, which leads to adhesion to intercellular adhesion molecule 1 immobilized on artificial surfaces. We sought to determine if anti-CD3 antibodies would increase adhesion of heart transplant recipient peripheral blood mononuclear cells to confluent human aortic endothelial cells by a similar mechanism. Peripheral blood mononuclear cells were incubated for 30 minutes with monoclonal CD3 or CD3 + CD18 antibody, before a 15-minute incubation with unstimulated human aortic endothelial cells. Mononuclear cell adhesion doubled after anti-CD3 antibody preincubation from 15.1 +/- 2.1 to 29.3 +/- 6.7 cells/high-power field (p = 0.002). This increase was abolished by coincubation with anti-CD18 (7.1 +/- 3 cells/high-power field; p = 0.0002). The major increase was the result of increased lymphocyte adhesion (3.4 +/- 0.6 to 14.8 +/- 6.7 cells/high-power field; p = 0.02); however, monocyte adhesion also increased from 11.7 +/- 1.5 to 14.5 +/- 1.6 cells/high-power field (p = 0.04). Anti-CD18 antibodies markedly reduced binding of both cell types. Cross-linking of the T-cell receptor by antibodies to CD3 causes acute adhesion of mononuclear cells (particularly lymphocytes) to arterial endothelium. Increased adhesion is mediated through CD18 (LFA-1/Mac-1).

Antibodies, Monoclonal↗