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A M Fogelman

Publications and source records attributed to A M Fogelman.

At least 37 records · Page 2Linked to original sources
PubMed1999

An evidence-based assessment of the NCEP Adult Treatment Panel II guidelines. National Cholesterol Education Program.

CONTEXT: The Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) was issued without the benefit of multiple recently published large clinical trials. OBJECTIVE: To analyze the panel's guidelines for treatment of high cholesterol levels in the context of currently available clinical trial results. DATA SOURCES: MEDLINE was searched for all English-language clinical trial data from 1993 through February 1999 relating to the effects of cholesterol treatment on cardiovascular clinical outcomes. STUDY SELECTION: Studies that were selected for detailed review assessed the effects of cholesterol lowering on either coronary events, coronary mortality, stroke, and/or total mortality, preferably by randomized, double-blind, placebo-controlled design. Selection was by consensus of a general internist, a lipid clinic director, and a researcher in atherosclerotic plaque biology. A core of 37 of the 317 initially screened studies were selected and used as the primary means by which to assess the guidelines. DATA EXTRACTION: By consensus of the group, only prespecified end points of trials were included, unless post hoc analysis addressed issues not studied elsewhere. DATA SYNTHESIS: Recent clinical trial data mostly support the Adult Treatment Panel II guidelines for cholesterol management. While existing trials have validated the target low-density lipoprotein cholesterol (LDL-C) goals in the report, studies are lacking that address mortality benefit from reduction below these levels. Few lipid-lowering trials have treated patients with low high-density lipoprotein cholesterol and/or elevated triglyceride levels with LDL-C levels at or below treatment goals. CONCLUSIONS: Lipid-lowering therapy generally should be more aggressively applied to patients with diabetes and/or at the time of coronary heart disease (CHD) diagnosis. The evidence for statin use in secondary CHD prevention in postmenopausal women outweighs current evidence for use of estrogen replacement in this setting. Further studies are needed to address the effects of lipid modification in primary prevention of CHD in populations other than middle-aged men and to study markers of lipid metabolism other than LDL-C.

Adult↗
PubMed1999

Structural identification of a novel pro-inflammatory epoxyisoprostane phospholipid in mildly oxidized low density lipoprotein.

One of the earliest steps in the development of the atherosclerotic lesion is the accumulation of monocyte/macrophages within the vessel wall. Oxidized lipids present in minimally modified-low density lipoproteins (MM-LDL) contribute to this process by activating endothelial cells to express monocyte-specific adhesion molecules and chemoattractant factors. A major focus of our group has been the isolation and characterization of the biologically active oxidized lipids in MM-LDL. We have previously characterized three oxidized phospholipids present in MM-LDL, atherosclerotic lesions of fat fed rabbits, and autoxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) that induced human aortic endothelial cells to adhere human monocytes in vitro. We have used sequential normal and reverse phase-high performance liquid chromatography to isolate various isomers of an oxidized phospholipid from autoxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine. The fatty acid in the sn-2 position of this biologically active isomer and its dehydration product was released by phospholipase A(2) and characterized. Hydrogenation with platinum(IV) oxide/hydrogen suggested a cyclic moiety, and reduction with sodium borohydride suggested two reducible oxygen-containing groups in the molecule. The fragmentation pattern produced by electrospray ionization-collision induced dissociation-tandem mass spectrometry was consistent with a molecule resembling an E-ring prostaglandin with an epoxide at the 5,6 position. The structure of this lipid was confirmed by proton nuclear magnetic resonance spectroscopy analysis of the free fatty acid isolated from the dehydration product of m/z 828.5. Based on these studies, we arrived at the structure of the biologically active oxidized phospholipids as 1-palmitoyl-2-(5, 6-epoxyisoprostane E(2))-sn-glycero-3-phosphocholine. The identification of this molecule adds epoxyisoprostanes to the growing list of biologically active isoprostanes.

Arachidonic Acids↗
PubMed1999

Role of group II secretory phospholipase A2 in atherosclerosis: 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase A2.

Some observations have suggested that the extracellular group IIa phospholipase A2 (sPLA2), previously implicated in chronic inflammatory conditions such as arthritis, may contribute to atherosclerosis. We have examined this hypothesis by studying transgenic mice expressing the human enzyme. Compared with nontransgenic littermates, the transgenic mice exhibited dramatically increased atherosclerotic lesions when maintained on a high-fat, high-cholesterol diet. Surprisingly, the transgenic mice also exhibited significant atherosclerotic lesions when maintained on a low-fat chow diet. Immunohistochemical staining indicated that sPLA2 was present in the atherosclerotic lesions of the transgenic mice. On both chow and atherogenic diets, the transgenic mice exhibited decreased levels of HDLs and slightly increased levels of LDLs compared with nontransgenic littermates. These data indicate that group IIa sPLA2 may promote atherogenesis, in part, through its effects on lipoprotein levels. These data also provide a possible mechanism for the observation that there is an increased incidence of coronary artery disease in many chronic inflammatory diseases.

Animals↗
PubMed1999

Role of group II secretory phospholipase A2 in atherosclerosis: 2. Potential involvement of biologically active oxidized phospholipids.

Secretory nonpancreatic phospholipase A2 (group II sPLA2) is induced in inflammation and present in atherosclerotic lesions. In an accompanying publication we demonstrate that transgenic mice expressing group II sPLA2 developed severe atherosclerosis. The current study was undertaken to determine whether 1 mechanism by which group II sPLA2 might contribute to the progression of inflammation and atherosclerosis is by increasing the formation of biologically active oxidized phospholipids. In vivo measurements of bioactive lipids were performed, and in vitro studies tested the hypothesis that sPLA2 can increase the accumulation of bioactive phospholipids. We have shown previously that 3 oxidized phospholipids derived from the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) stimulated endothelial cells to bind monocytes, a process that is known to be an important step in atherogenesis. We now show that these 3 biologically active phospholipids are significantly increased in livers of sPLA2 transgenic mice fed a high-fat diet as compared with nontransgenic littermates. We present in vitro evidence for several mechanisms by which these phospholipids may be increased in sPLA2 transgenics. These studies demonstrated that polyunsaturated free fatty acids, which are liberated by sPLA2, increased the formation of bioactive phospholipids in LDL, resulting in increased ability to stimulate monocyte-endothelial interactions. Moreover, sPLA2-treated LDL was oxidized by cocultures of human aortic endothelial cells and smooth muscle cells more efficiently than untreated LDL. Analysis by electrospray ionization-mass spectrometry revealed that the bioactive phospholipids, compared with unoxidized PAPC, were less susceptible to hydrolysis by human recombinant group II sPLA2. In addition, HDL from the transgenic mice and human HDL treated with recombinant sPLA2 in vitro failed, in the coculture system, to protect against the formation of biologically active phospholipids in LDL. This lack of protection may in part relate to the decreased levels of paraoxonase seen in the HDL isolated from the transgenic animals. Taken together, these studies show that levels of biologically active oxidized phospholipids are increased in sPLA2 transgenic mice; they also suggest that this increase may be mediated by effects of sPLA2 on both LDL and HDL.

Animals↗
PubMed1998

Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis.

Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs). To study the role of PON1 in vivo, we created PON1-knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1-knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1-null mice were more susceptible to atherosclerosis than their wild-type littermates.

Animals↗
PubMed1998

Paraoxonase and coronary heart disease.

Paraoxonase (PON1) hydrolyses organophosphate insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. Human PON1 has two genetic polymorphisms giving rise to amino-acid substitutions at positions 55 and 192. The 192 polymorphism is the major determinant of the PON1 activity polymorphism towards organophosphates. However, the 55 polymorphism also modulates activity. Ex vivo, the PON1 polymorphisms are important in determining the capacity of HDL to protect LDL against oxidative modification in vitro and this may explain the relationship between the PON1 alleles and coronary heart disease in case-control studies. In recent case-control studies serum PON1 concentration and activity were also found to be decreased in coronary heart disease (CHD) independent of the PON1 polymorphism, and in diabetes serum PON1 specific activity decrease is also independent of the PON1 genetic polymorphism. HDL from transgenic mice lacking PON1 fails to protect LDL against oxidative modification. Thus PON1 may be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolysing phospholipid and cholesteryl-ester hydroperoxides.

Animals↗
PubMed1998

High density associated enzymes: their role in vascular biology.

Enzymes associated with circulating HDL include lecithin: cholesterol acyl transferase, phospholipid transfer protein, cholesterol ester transfer protein, paraoxonase 1 and platelet activating factor acetylhydrolase. Together with lipoprotein lipase and hepatic lipase these enzymes produce important lipoprotein remodeling and modulate their structure and function and therefore their role in artery wall metabolism.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1997

Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.

Heme catabolic processes produce the antioxidants biliverdin and bilirubin, as well as the potent prooxidant free iron. Since these products have opposing effects on oxidative stress, it is not clear whether heme catabolism promotes or inhibits inflammatory processes, including atherosclerotic lesion formation. Heme oxygenase (HO) catalyzes the rate-limiting step of heme catabolism. We used cocultures of human aortic endothelial cells and smooth muscle cells to examine the possible role of HO in early atherosclerosis. Heme oxygenase-1 (HO-1), the inducible isoform of HO, was highly induced by mildly oxidized LDL, and augmented induction was observed with hemin pretreatment. This augmented HO-1 induction resulted in the reduction of monocyte chemotaxis in response to LDL oxidation. Conversely, inhibition of HO by a specific inhibitor, Sn-protoporphyrin IX, enhanced chemotaxis. Furthermore, pretreatment with biliverdin or bilirubin, the products of HO, reduced chemotaxis. Oxidized phospholipids in the mildly oxidized LDL appear to be responsible for HO-1 induction, since oxidized but not native arachidonic acid-containing phospholipids also induced HO-1. These results suggest that HO-1 induced by mildly oxidized LDL may protect against the induction of inflammatory responses in artery wall cells through the production of the antioxidants biliverdin and bilirubin.

Bilirubin↗
PubMed1997

Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles.

Previous studies showed that transgenic mice overexpressing either apolipoprotein AI (apoAI) or apolipoprotein AII (apoAII), the major proteins of HDL, exhibited elevated levels of HDL cholesterol, but, whereas the apoAI-transgenic mice were protected against atherosclerosis, the apoAII-transgenic mice had increased lesion development. We now examine the basis for this striking functional heterogeneity. HDL from apoAI transgenics exhibited an enhanced ability to promote cholesterol efflux from macrophages, but HDL from apoAII transgenics and nontransgenics were not discernibly different in efflux studies. In contrast with HDL from nontransgenics and apoAI transgenics, HDL from the apoAII transgenics were unable to protect against LDL oxidation in a coculture model of the artery wall. Furthermore, HDL taken from apoAII-transgenic mice, but not HDL taken from either the apoAI transgenics or nontransgenic littermate controls, by itself stimulated lipid hydroperoxide formation in artery wall cells and induced monocyte transmigration, indicating that the apoAII-transgenic HDL were in fact proinflammatory. This loss in the ability of the apoAII-transgenic HDL to function as an antioxidant/antiinflammatory agent was associated with a decreased content of paraoxonase, an enzyme that protects against LDL oxidation. Reconstitution of the apoAII transgenic HDL with purified paraoxonase restored both paraoxonase activity and the ability to protect against LDL oxidation. We conclude that overexpression of apoAII converts HDL from an anti- to a proinflammatory particle and that paraoxonase plays a role in this transformation.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1997

Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo.

Entry of monocytes into the vessel wall is an important event in atherogenesis. Previous studies from our laboratory suggest that oxidized arachidonic acid-containing phospholipids present in mildly oxidized low density lipoproteins (MM-LDL) can activate endothelial cells to bind monocytes. In this study, biologically active oxidized arachidonic acid-containing phospholipids were produced by autoxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) and analyzed by liquid chromatography and electrospray ionization mass spectrometry in conjuction with biochemical derivatization techniques. We have now determined the molecular structure of two of three molecules present in MM-LDL and Ox-PAPC that induce monocyte-endothelial interactions. These lipids were identified as 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (m/z 594.3) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (m/z 610.2). These two molecules were produced by unambiguous total synthesis and found to be identical by analytical techniques and bioactivity assays to those present in MM-LDL and Ox-PAPC. Evidence for the importance of all three oxidized phospholipids in vivo was suggested by their presence in fatty streak lesions from cholesterol-fed rabbits and by their immunoreactivity with natural antibodies present in ApoE null mice. Overall, these studies suggest that specific oxidized derivatives of arachidonic acid-containing phospholipids may be important initiators of atherogenesis.

Animals↗
PubMed1997

Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio.

We have examined the effects of mildly oxidized LDL and atherosclerosis on the levels of two proteins associated with HDL; apolipoprotein J (apoJ), and paraoxonase (PON). On an atherogenic diet, PON activity decreased by 52%, and apoJ levels increased 2.8-fold in fatty streak susceptible mice, C57BL/6J (BL/6), but not in fatty streak resistant mice, C3H/HeJ (C3H). Plasma PON activity was also significantly decreased, and apoJ levels were markedly increased in apolipoprotein E knockout mice on the chow diet, resulting in a 9.2-fold increase in the apoJ/PON ratio as compared to controls. Furthermore, a dramatic increase in the apoJ/PON ratio (over 100-fold) was observed in LDL receptor knockout mice when they were fed a 0.15%-cholesterol-enriched diet. Injection of mildly oxidized LDL (but not native LDL) into BL/6 mice (but not in C3H mice) on a chow diet resulted in a 59% decrease in PON activity (P < 0.01) and a 3.6-fold increase in apoJ levels (P < 0.01). When an acute phase reaction was induced in rabbits, or the rabbits were placed on an atherogenic diet, hepatic mRNA for apoJ was increased by 2.7-fold and 2.8-fold, respectively. Treatment of HepG2 cells in culture with mildly oxidized LDL (but not native LDL) resulted in reduced mRNA levels for PON (3.0-fold decrease) and increased mRNA levels for apoJ (2.0-fold increase). In normolipidemic patients with angiographically documented coronary artery disease who did not have diabetes and were not on lipid-lowering medication (n = 14), the total cholesterol/HDL cholesterol ratio was 3.1+/-0.9 as compared to 2.9+/-0.4 in the controls (n = 19). This difference was not statistically significant. In contrast, the apoJ/PON ratio was 3.0+/-0.4 in the patients compared to 0.72+/-0.2 in the controls (P < 0.009). In a subset of these normolipidemic patients (n = 5), the PON activity was low (48+/-6.6 versus 98+/-17 U/ml for controls; P < 0.009), despite similar normal HDL levels, and the HDL from these patients failed to protect against LDL oxidation in co-cultures of human artery wall cells. We conclude that: (a) mildly oxidized LDL can induce an increased apoJ/PON ratio, and (b) the apoJ/PON ratio may prove to be a better predictor of atherosclerosis than the total cholesterol/HDL cholesterol ratio.

Animals↗
PubMed1997

Monocyte binding to endothelial cells induced by oxidized phospholipids present in minimally oxidized low density lipoprotein is inhibited by a platelet activating factor receptor antagonist.

Our group has previously demonstrated that oxidized phospholipids derived from mildly oxidized low density lipoprotein (MM-LDL) or oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) increase monocyte-endothelial interactions. There are indications that the effects of these phospholipids are receptor mediated. Oxidized phospholipids have previously been shown to activate cells via the platelet activating factor (PAF) receptor, therefore, we pretreated human aortic endothelial cells (HAECs) with a PAF-receptor antagonist (WEB 2086) prior to treatment with oxPAPC. WEB 2086 inhibited monocyte binding to endothelial cells induced by oxPAPC (200 micrograms/ml) at concentrations from 1 nM to 10 microM, but had no effect on the induction of monocyte binding induced by lipopolysaccharide (LPS). We were able to isolate and identify several active oxidized phospholipids by combined normal phase high performance liquid chromatography (HPLC) and electrospray mass spectrometry (LC/MS). The induction of monocyte binding to HAECs by two of these partially purified phospholipids was totally abolished by the pretreatment of HAECs with WEB 2086 (100 nM). PAF itself, however, when tested at concentrations from 10 nM to 10 microM had no effect on monocyte binding. These results suggest that several of the oxidized phospholipids present in MM-LDL and oxPAPC induce monocyte binding through a receptor which is perhaps distinct from the PAF-receptor, but can be blocked by the PAF-receptor antagonist WEB 2086.

Aorta↗
PubMed1996

Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis.

T cell cytokines are known to play a major role in determining protection and pathology in infectious disease. It has recently become clear that IL-12 is a key inducer of the type 1 T cell cytokine pattern characterized by production of IFN-gamma. Conversely, IL-10 down-regulates IL-12 production and type 1 cytokine responses. We have investigated whether IL-12 and IL-10 might be involved in a chronic inflammatory reaction, atherosclerosis. In atherosclerotic plaques, we found strong expression of IFN-gamma but not IL-4 mRNAs as compared to normal arteries. IL-12 p40 mRNA and IL-12 p70 protein were also found to be abundant in atherosclerotic plaques. IL-12 was induced in monocytes in vitro in response to highly oxidized LDL but not minimally modified LDL. The cross-regulatory role of IL-10 was indicated by the expression of IL-10 in some atherosclerotic lesions, and the demonstration that exogenous rIL-10 inhibited LDL-induced IL-12 release. These data suggest that the balance between IL-12 and IL-10 production contributes to the level of immune-mediated tissue injury in atherosclerotsis.

Aorta↗
PubMed1996

Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model.

In an effort to identify genetic factors contributing to atherogenesis, we have studied inbred strains of mice that are susceptible (C57BL/6J) and resistant (C3H/HeJ) to diet-induced aortic fatty streak lesions. When maintained on a low-fat diet, HDL isolated from both strain C57BL/6J (B6) and C3H/HeJ (C3H) mice protect against LDL oxidation in a coculture model of the artery wall. However, when maintained on an atherogenic diet high in fat and cholesterol, the HDL isolated from B6 mice lose the capacity to protect, whereas HDL from C3H mice protect equally well. Associated with the loss in the ability of HDL to protect is a decrease in the activity of serum paraoxonase, a serum esterase carried on HDL that has previously been shown to protect against LDL oxidation in vitro. The levels of paraoxonase mRNA decreased in B6 mice upon challenge with the atherogenic diet but increased in C3H, indicating that paraoxonase production is under genetic control. In a set of recombinant inbred strains derived from the B6 and C3H parental strains, low paraoxonase mRNA levels segregated with aortic lesion development, supporting a role for paraoxonase in atherogenesis.

Amino Acid Sequence↗
PubMed1996

Preserving medical schools' academic mission in a competitive marketplace.

To gain a better understanding of the effects on medical schools of transformations in medical practice, science, and public expectations, the AAMC in 1994 formed the Advisory Panel on the Mission and Organization of Medical Schools and appointed six working groups to address relevant issues. This article is a report of the findings of the Working Group on Preserving Medical Schools' Academic Mission in a Competitive Marketplace, which was charged with exploring how medical schools could acquire and/or preserve an adequate patient base for teaching, research, and income generation in a competitive marketplace. The other groups' reports will appear in future issues of Academic Medicine. To understand the diversity of approaches that schools have taken to achieve this goal and to preserve their missions, the group interviewed representatives of nine medical schools, selected to represent a cross section of U.S. medical schools. The interviews took place on four occasions between June 1995 and March 1996. The information and comments shared by participants helped the working group gain insight into the fundamental issues it had been charged to address, including those of new delivery structures, what value schools offer to delivery structures, how education and research can be incorporated and supported financially, possible new pressures on relationships between medical schools and teaching hospitals, changes in faculty physicians' employment relationships and terms, and the role of the medical school in graduate medical education. In collecting and analyzing the data, the working group focused on the distinction between protecting an institution's existing enterprise and preserving an institution's core mission. This article gives a detailed overview of the information and comments each school presented, organized under the appropriate question. The working group's conclusions and commentaries on the findings follow. An appendix presents more detailed summaries of the schools' presentations, organised as case studies. The picture that emerges is complex. The working group concluded that medical schools will take a variety of approaches to define and preserve their missions. Most, but not all, medical schools will be able to secure the patient bases necessary to fulfill their missions even in a competitive marketplace. However, the nature of many of the schools is likely to change, and it is not clear whether the core missions of education and research will continue at their present levels at all schools.

Costs and Cost Analysis↗
PubMed1996

The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture.

Recent data support the hypothesis that the fatty streak develops in response to specific phospholipids contained in LDL that become trapped in the artery wall and become oxidized as a result of exposure to the oxidative waste of the artery wall cells. The antioxidants present within both LDL and the microenvironments in which LDL is trapped function to prevent the formation of these biologically active, oxidized lipids. Enzymes associated with LDL and HDL (eg, platelet activating factor acetylhydrolase) or with HDL alone (eg, paraoxonase) destroy these biologically active lipids. The regulation and expression of these enzymes are determined genetically and are also significantly modified by environmental influences, including the acute-phase response or an atherogenic diet. The balance of these multiple factors leads to an induction or suppression of the inflammatory response in the artery wall and determines the clinical course.

Animals↗
PubMed1995

Pathogenesis of atherosclerosis.

The earliest lesion in the development of an atherosclerotic plaque is the fatty streak. This chronic inflammatory reaction results from a sequence of events that begins with the trapping of low density lipoprotein (LDL) in the subendothelial space of the artery wall. The trapped LDL is seeded with oxidative species released by the overlying endothelium, and lipid oxidation is initiated within the LDL particle. Some of the lipids that result lead to the activation of NFkB-like transcription factors that cause the expression of genes whose protein products mediate monocyte binding, monocyte chemotaxis into the subendothelial space, and conversion into macrophages. At least 1 major gene modulates the oxidation of LDL lipids and/or the biologic response to these lipids. The inverse relation between high density lipoprotein (HDL) and atherosclerotic events may in part be due to enzymes associated with HDL that destroy the biologically active lipids generated in LDL.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗