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Biomedical subjects

A M Fogelman

Publications and source records attributed to A M Fogelman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics.

The clinical events resulting from atherosclerosis are directly related to the oxidation of lipids in LDLs that become trapped in the extracellular matrix of the subendothelial space. These oxidized lipids activate an NF kappa B-like transcription factor and induce the expression of genes containing NF kappa B binding sites. The protein products of these genes initiate an inflammatory response that initially leads to the development of the fatty streak. The progression of the lesion is associated with the activation of genes that induce arterial calcification, which changes the mechanical characteristics of the artery wall and predisposes to plaque rupture at sites of monocytic infiltration. Plaque rupture exposes the flowing blood to tissue factor in the lesion, and this induces thrombosis, which is the proximate cause of the clinical event. There appear to be potent genetically determined systems for preventing lipid oxidation, inactivating biologically important oxidized lipids, and/or modulating the inflammatory response to oxidized lipids that may explain the differing susceptibility of individuals and populations to the development of atherosclerosis. Enzymes associated with HDL may play an important role in protecting against lipid oxidation in the artery wall and may account in part for the inverse relation between HDL and risk for atherosclerotic clinical events.

Arteriosclerosis↗
PubMed1995

Genetic control of the inflammatory response induced by oxidized lipids.

The fatty streak begins with entrapment of apolipoprotein B (apoB)-containing lipoproteins in the subendothelial space at susceptible sites in the arterial wall. Minimally oxidized low density lipoprotein (MM-LDL) induces endothelial cells to bind monocytes and produce message and protein for monocyte chemotactic protein-1 and macrophage colony-stimulating factor. In culture, human endothelial and smooth muscle cells in arterial wall configuration sequester LDL, protecting it from antioxidants and giving rise to MM-LDL-like species. In mice, MM-LDL induces monocyte binding at susceptible aortic sites; the monocytes may then differentiate into macrophages that release reactive oxygen and active aldehydes, resulting in highly oxidized LDL leading to foam cell formation. Feeding mice an atherogenic diet induces expression of several inflammatory and oxidative stress genes, including serum amyloid A, which binds exclusively to HDL. This may contribute to a decrease in protective HDL levels seen in mice susceptible to fatty streak formation.

Animals↗
PubMed1995

Stimulation of Gs and inhibition of Gi protein functions by minimally oxidized LDL.

We have previously shown that treatment of aortic endothelial cells with minimally oxidized LDL (MM-LDL) induces their interaction with monocytes but not neutrophils and that these induced responses are associated with increased cAMP levels. Here we studied the mechanism of by which MM-LDL elevates cAMP levels. Treatment of human aortic endothelial cells with MM-LDL resulted in a saturable dose-dependent increase in cAMP levels. Studies using a combination of pertussis toxin and MM-LDL suggested that part of the cAMP increase was due to the stimulation of Gs complexes. Studies with pertussis toxin-treated membranes in which Gi was completely inhibited were used to directly address the effect of MM-LDL on the Gs pathway. MM-LDL and an oxidized lipid (palmitoyl arachidonyl phosphatidylcholine), the effects of which mimic those of MM-LDL, caused a 40% to 100% increase in cAMP levels in these isolated membranes that was augmented by GTP, thus showing Gs stimulation. These results also show that MM-LDL increases cAMP levels by inhibiting Gi. MM-LDL inhibited ADP ribosylation of Gi by about 30% and completely abolished the ability of serotonin to interact with Gi complexes, whereas direct activation of Gi by mastoparan was not inhibited. This observation suggests that MM-LDL interferes with the interaction of Gi molecules with inhibitory receptors. There was no direct effect of MM-LDL on adenylate cyclase. Overall, these studies show that MM-LDL increases cAMP levels both by stimulating Gi and inhibiting Gi complexes.

Adenylyl Cyclases↗
PubMed1995

Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein.

Mildly oxidized low density lipoprotein (MM-LDL) produced by oxidative enzymes or cocultures of human artery wall cells induces endothelial cells to produce monocyte chemotactic protein-1 and to bind monocytes. HDL prevents the formation of MM-LDL by cocultures of artery wall cells. Using albumin treatment and HPLC we have isolated and partially characterized bioactive oxidized phospholipids in MM-LDL. Platelet activating factor-acetylhydrolase (PAF-AH), a serine esterase, hydrolyzes short chain acyl groups esterified to the sn-2 position of phospholipids such as PAF and particular oxidatively fragmented phospholipids. Treatment of MM-LDL with PAF-AH (2-4 x 10(-2) U/ml) eliminated the ability of MM-LDL to induce endothelial cells to bind monocytes. When HDL protected against the formation of MM-LDL by cocultures, lysophosphatidylcholine was detected in HDL; whereas when HDL was pretreated with diisopropyl fluorophosphate, HDL was no longer protective and lysophosphatidylcholine was undetectable. HPLC analysis also revealed that the active oxidized phospholipid species in MM-LDL had been destroyed after PAF-AH treatment. In addition, treatment of MM-LDL with albumin removed polar phospholipids that, when reisolated, induced monocyte binding to endothelial cells. These polar phospholipids, when treated with PAF-AH, lost biological activity and were no longer detected by HPLC. These results suggest that PAF-AH in HDL protects against the production and activity of MM-LDL by facilitating hydrolysis of active oxidized phospholipids to lysolipids, thereby destroying the biologically active lipids in MM-LDL.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1995

Lipid-induced changes in intracellular iron homeostasis in vitro and in vivo.

Iron promotes cellular damage via its capacity to catalyze hydroxyl radical formation and by peroxidation of unsaturated lipids. The major cellular iron storage depot, ferritin, acts as a critical antioxidant defense by sequestering unbound or "free" iron, limiting its participation in damaging oxidative reactions. In this study, we investigated the relationship between LDL modified by artery wall cells and the regulation of intracellular free iron levels in the mouse model and in a human aortic endothelial and smooth muscle cell coculture system. We found in response to an atherogenic diet, fatty streak-resistant C3H/HeJ mice exhibited higher levels of liver apoferritin and lower intracellular concentrations of free iron than did fatty streak-susceptible C57 BL/6J mice. Also, ferritin repressor protein mRNA was not significantly suppressed after 15 wk on the atherogenic diet in female C57BL/6J mice, which exhibit the most extensive fatty streak formation, but was significantly reduced in C3H/HeJ mice. Iron loading of coculture cells resulted in elevations of cellular free iron and enhanced LDL-induced monocyte transmigration. Pretreatment of cells with apoferritin completely abolished iron-induced LDL modification. Addition of LDL to cocultures resulted in elevations in lipid peroxidation products, intracellular free iron, apoferritin mRNA expression, and apoferritin synthesis, suggesting a possible relationship between the oxidative modification of LDL and iron metabolism.

Animals↗
PubMed1995

Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures.

We previously reported that high density lipoprotein (HDL) protects against the oxidative modification of low density lipoprotein (LDL) induced by artery wall cells causing these cells to produce pro-inflammatory molecules. We also reported that enzyme systems associated with HDL were responsible for this anti-inflammatory property of HDL. We now report studies comparing HDL before and during an acute phase response (APR) in both humans and a croton oil rabbit model. In rabbits, from the onset of APR the protective effect of HDL progressively decreased and was completely lost by day three. As serum amyloid A (SAA) levels in acute phase HDL (AP-HDL) increased, apo A-I levels decreased 73%. Concomitantly, paraoxonase (PON) and platelet activating factor acetylhydrolase (PAF-AH) levels in HDL declined 71 and 90%, respectively, from days one to three. After day three, there was some recovery of the protective effect of HDL. AP-HDL from human patients and rabbits but not normal or control HDL (C-HDL) exhibited increases in ceruloplasmin (CP). This increase in CP was not seen in acute phase VLDL or LDL. C-HDL incubated with purified CP and re-isolated (CP-HDL), lost its ability to inhibit LDL oxidation. Northern blot analyses demonstrated enhanced expression of MCP-1 in coculture cells treated with AP-HDL and CP-HDL compared to C-HDL. Enrichment of human AP-HDL with purified PON or PAF-AH rendered AP-HDL protective against LDL modification. We conclude that under basal conditions HDL serves an anti-inflammatory role but during APR displacement and/or exchange of proteins associated with HDL results in a pro-inflammatory molecule.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1995

Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein.

Our group has previously demonstrated that oxidized phospholipids in mildly oxidized LDL (MM-LDL) produced by oxidation with lipoxygenase, iron, or cocultures of artery wall cells increase monocyte-endothelial interactions and this sequence of events is blocked by HDL. To obtain further insight into the mechanism by which HDL abolishes the activity of MM-LDL we investigated the effect of the HDL-associated ester hydrolase paraoxonase (PON). Treatment of MM-LDL with purified PON significantly reduced the ability of MM-LDL to induce monocyte-endothelial interactions. Inactivation of PON by pretreating HDL with heat or EDTA reduced the ability of HDL to inhibit LDL modification. HPLC analysis of phospholipids isolated from MM-LDL before and after treatment with purified PON showed that the 270 nm absorbance of phospholipids was decreased, while no effect was observed on 235 nm absorbance. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and specific fractions of Ox-PAPC isolated by HPLC induced the same monocyte-endothelial interactions as did MM-LDL. Biologically active and inactive HPLC fractions of Ox-PAPC were compared by fast atom bombardment-mass spectrometry which revealed that active fractions possessed ions with a mass to charge [correction of change] ratio greater than native PAPC by multiples of 16 D suggesting the addition of 3 and 4 oxygen atoms to PAPC. Comparison of Ox-PAPC by fast atom bombardment-mass spectrometry before and after PON treatment showed that PON destroyed these multi-oxygenated molecules found in biologically active fractions of Ox-PAPC. These results suggest that PON in HDL may protect against the induction of inflammatory responses in artery wall cells by destroying biologically active lipids in mildly oxidized LDL.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1994

Strategies for training generalists and subspecialists.

A strategy is proposed for attracting trainees to careers in general internal medicine coupled with a program that attracts a smaller number of trainees to research careers without attracting trainees into careers in the practice of the subspecialties. A novel training track analogous to the Medical Scientist Training Program, the Specialty Training and Academic Research (STAR) Program has been established. It is anticipated that within the next 5 years, 80% of the trainees in the department of medicine at the University of California, Los Angeles, Medical Center will be training for practice in general internal medicine; the remaining 20% will be enrolled in the STAR Program.

Career Choice↗
PubMed1994

Partial characterization of leukocyte binding molecules on endothelial cells induced by minimally oxidized LDL.

Treatment of rabbit aortic endothelial cells, human umbilical vein endothelial cells, and human aortic endothelial cells for 4 hours with minimally oxidized low-density lipoprotein (MM-LDL) induced the adhesion of monocytes but not neutrophils or lymphocytes to these cells. This induction was blocked by inhibitors of glycoprotein synthesis (cycloheximide and tunicamycin), and binding was abolished by treatment of cells with low levels of trypsin, suggesting that the binding molecule(s) is a protein. There was no increase in binding of antibodies to E-selectin, vascular cell adhesion molecule-1 (VCAM-1), or intercellular adhesion molecule-1 (ICAM-1) after treatment of cells with MM-LDL. Treatment of endothelial cells with Fab fragments of antibody to monocyte chemotactic protein-1 or to fibronectin did not block monocyte binding. Several sugars (lactose-1-phosphate, maltose-1-phosphate, and N-acetylglucosamine) inhibited monocyte binding to cells treated with MM-LDL, but binding was not blocked by mannose-6-phosphate, fructose-6-phosphate, glucose-1-phosphate, or glucose-6-phosphate. EDTA or EGTA treatment inhibited binding, which was restored by adding either calcium or magnesium. We conclude that the binding of monocytes to endothelial cells induced by a 4-hour treatment with MM-LDL is caused by a binding molecule(s) other than E-selectin, VCAM-1, or ICAM-1 and that carbohydrate chains on the monocytes or the endothelium play a role in binding.

Cell Adhesion↗
PubMed1994

Serum amyloid A protein family. Differential induction by oxidized lipids in mouse strains.

During inflammation, serum amyloid A (SAA) protein increases up to 1000-fold and can become a major component of high-density lipoprotein (HDL). We have identified a new apolipoprotein molecule (SAA5) as a distinct member of the SAA family. It differs from the inflammatory isotypes (SAA1, SAA2, and SAA3) not only in structure but in the fact that it is constitutive on normal HDL where it accounts for more than 90% of total SAA. Whereas all members of the SAA family, including SAA5, responded to endotoxin administration, SAA5 contrasted with other SAAs in its resistance to induction either by a high-fat, high-cholesterol atherogenic diet or the injection of mildly oxidized LDL (MM-LDL). These data provide further evidence that the induction of inflammatory molecules by oxidized lipids is selective. In atherosclerosis-susceptible C57BL/6 mice and atherosclerosis-resistant C3H/HeJ mice, the inflammatory SAA isotypes (SAA1, SAA2, and SAA3) responded in a strain-specific manner to oxidized lipids either generated with feeding of the atherogenic diet or introduced by MM-LDL injection. We hypothesize that the constitutive SAA5 molecules on normal HDL may contribute to its normal physiological role and that the dramatic induction of the inflammatory SAA subfamily equips the particle for an altered yet related functional role appropriate to the inflammatory state.

Animals↗
PubMed1994

Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice.

In a previous survey of inbred mouse strains on an atherogenic diet, we observed that the susceptibility to aortic atherosclerotic lesion formation was associated with the accumulation of lipid peroxidation products, induction of inflammatory genes, and the activation of NF-kB-like transcription factors (Liao, F., A. Andalibi, F. C. deBeer, A. M. Fogelman, and A.J. Lusis. 1993. J. Clin. Invest. 91:2572-2579). We hypothesized that the inflammation-related processes were stimulated by oxidized lipids, since injection of minimally oxidized LDL (MM-LDL) activated the same set of genes. We now report that the induction of inflammatory genes and activation of NF-kB-like transcription factors cosegregate with aortic atherosclerotic lesion formation in BXH recombinant inbred strains derived from parental C57BL/6J (susceptible) and C3H/HeJ (resistant) mice. In addition, the accumulation of hepatic conjugated dienes exhibited a significant correlation with inflammatory gene activation. These results provide strong evidence for the role of inflammatory mediators inducible by oxidative stress in atherogenesis. They also suggest that a major gene contributing to aortic lesion development in this mouse model, designated Ath-1, may control either the accumulation of lipid peroxides in tissues or the cellular responses to such lipid peroxides.

Animals↗
PubMed1994

Role of the GRO family of chemokines in monocyte adhesion to MM-LDL-stimulated endothelium.

We have previously shown that treatment of endothelial cells with minimally modified LDL (MM-LDL) induces the binding of monocytes to unknown endothelial receptor molecules. We now report that a member of the GRO family of chemokines plays a role in MM-LDL-induced monocyte binding. A cDNA library made from rabbit aortic endothelial cells (RAEC) treated with MM-LDL was expression screened for molecules inducing binding of a human monocyte cell line (THP-1). A cDNA was isolated with 75% homology to GRO. GRO mRNA levels were significantly elevated after exposure of RAEC or human aortic endothelial cells (HAEC) to MM-LDL. HAEC treated with MM-LDL displayed an increase in a surface-associated protein that bound to antibody against GRO despite low levels of GRO in the medium. Antibody to GRO significantly inhibited the binding of monocytes to MM-LDL-treated RAEC and HAEC. The increase in GRO expression and monocyte binding were reduced by incubating MM-LDL-treated endothelial cells with heparin (in a method that releases heparan sulfate bound molecules from the cell surface). These results suggest that GRO related chemokines are bound to the surface of MM-LDL-treated endothelial cells and may contribute to the monocyte adhesion induced by MM-LDL.

Amino Acid Sequence↗
PubMed1994

Recipient mononuclear cell recognition and adhesion to graft endothelium after human cardiac transplantation. Lymphocyte recognition leads to monocyte adhesion.

Transendothelial migration of mononuclear cells is crucial in the development of allograft rejection and transplant coronary disease. Adhesion of circulating cells to endothelium is the initial step in transendothelial migration. Human aortic endothelial cell cultures were established from aortic tissue harvested at the time of organ donation for cardiac transplantation which allowed specific recipient mononuclear cell-graft endothelial interactions to be studied. Confluent untreated endothelial cells were incubated with recipient mononuclear cells for 15 min to assess adhesion. Adhesion of recipient mononuclear cells to endothelium derived from their graft was threefold higher than adhesion to nonspecific endothelium (93 +/- 20 vs. 30 +/- 11 cells/high power field, P < 0.005). Graft-specific adhesion was inhibited by preincubation of the endothelium with antibodies to class I HLA (34 +/- 16 cells/high power field, P < 0.005). Immunofluorescence performed after adhesion showed that 73 +/- 6% of both specific and nonspecific adherent cells were monocytes. The use of purified lymphocyte and monocyte preparations showed that graft-specific lymphocytes induce unrelated monocytes to become adherent. These results suggest that lymphocytes are primed in vivo to recognize endothelium derived from their graft which leads to a rapid increase in lymphocyte and monocyte adhesion. Such allo-recognition may involve endothelial class I HLA molecules.

CD3 Complex↗
PubMed1994

Impact of managed care on departments of internal medicine.

Economic forces make managed care inevitable. Despite the complexities of adapting to this new paradigm, if departments of internal medicine take a leadership role in the medical enterprise and successfully develop a primary care component while reducing their reliance on subspecialty medicine, it is likely that because of its size and the talents of its faculty, IM departments will survive and even thrive in a managed care environment.

Education, Medical, Graduate↗
PubMed1993

A new anti-inflammatory leucine derivative, NPC-15669, inhibits growth of cultured human aortic smooth muscle cells.

We have observed that NPC-15669, a leucine derivative with anti-inflammatory activity, reduced the proliferation of human aortic smooth muscle cells (HASMCs) in culture. We used a colorimetric assay and tritiated thymidine to measure the cell density and proliferation of HASMC cultures treated with this agent. We also studied the effect of NPC-15669 on the proliferation and migration of human aortic endothelial cells (HAECs). Subconfluent HASMC cultures were growth arrested for 2 days. On the third day, growth was stimulated with either growth media (medium M199 containing 10% fetal bovine serum [FBS]), human platelet-derived growth factor (hPDGF), or fibroblast growth factor (FGF) in the absence or presence of NPC-15669 (0.1-50 microM). Regardless of the stimulating agent for HASMCs (FBS, hPDGF, or FGF), NPC-15669 at concentrations of 10-25 microM caused a significant reduction in thymidine incorporation (36.7% and 77.2% in 10 microM and 25 microM, respectively; p < 0.005) and cell density (25-87%, p < 0.001) compared with control. NPC-15669 did not, however, have an effect on the rate of proliferation or migration of HAECs, even at concentrations up to 50 microM. Two other anti-inflammatory agents, aspirin and dexamethasone, caused substantially and significantly less inhibition, even at high concentrations (50 and 25 microM, respectively). This study demonstrates that in vitro, NPC-15669 significantly inhibits HASMC proliferation but has no effect on proliferation or migration of HAECs.

Anti-Inflammatory Agents, Non-Steroidal↗