Andrew Nicholson

New York University

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Document Type

Co-Authors

David P. Hajjar

Cornell University

Jihong Han

Nankai University

Antonio M. Gotto

Cornell University

D P Hajjar

Cornell University

Scott E. Sherman

VA NY Harbor Healthcare System

Maria Febbraio

University of Alberta

Barbara D. Summers

Weill Cornell Medicine

Xiaoye Zhou

Shenzhen MSU-BIT University

Roy L. Silverstein

Medical College of Wisconsin

Omar El‐Shahawy

New York University

Cooperative Institutions

University of Leeds

871

British Heart Foundation

661

Leeds Teaching Hospitals NHS Trust

240

University of Belgrade

149

Newcastle University

Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital

European Society of Cardiology

Imperial College London

New York University

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Dihydropyridine calcium antagonist modulates cholesterol metabolism and eicosanoid biosynthesis in vascular cells

Journal of Cellular Biochemistry (1992)

Andrew Nicholson Orli R. Etingin Kenneth B. Pomerantz Barbara D. Summers Karen J. Friday

Recent clinical studies have shown that calcium channel blockers can retard and possibly reduce the angiographic progression of coronary artery disease. Calcium channel blockers also inhibit dietary-induced atherosclerosis in animal models of this disease. In this study, we delineate potential cellular and molecular mechanisms by which nicardipine, a dihydropyridine calcium antagonist, may alter lipoprotein and cholesterol trafficking, affect the regulatory signal transduction pathways involved in accelerating cholesteryl ester (CE) catabolism in vascular smooth muscle cells, and modulate cell-cell interactions of vascular and inflammatory cells. We demonstrate in arterial smooth muscle cells that nicardipine increases 1) LDL binding, uptake, and degradation, 2) RNA transcript levels for the LDL receptor, 3) CE catabolic activity, 4) PGI2 release, and 5) RNA transcript levels for cyclooxygenase. Furthermore, nicardipine blocked cytokine-induced monocyte adhesion to endothelial cells and smooth muscle cells. Taken together, these findings support the hypothesis that nicardipine may function as an anti-atherosclerotic agent by promoting CE catabolism and cholesterol clearance and by reducing monocyte adhesion to the activated endothelium.

Eicosanoid metabolism

10.1002/jcb.240480408

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Citations (8)

Protocol for a prospective, randomized, controlled trial of Mental Contrasting with Implementation Intentions (MCII) to enhance the effectiveness of VA's MOVE! weight management program: WOOP (Wish, Outcome, Obstacle, Plan) VA

Contemporary Clinical Trials (2024)

Sarvenaz Vandyousefi Gabriele Oettingen Sandra Wittleder Tannaz Moin Victoria Sweat

10.1016/j.cct.2024.107523

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478-P: Preventing Peripheral Neuropathy in Adults with Type 2 Diabetes—A Meta-analysis of Randomized Clinical Trials

Diabetes (2024)

SOPHIA GUNAWAN THERESA ANTONY Andrew Nicholson Sundar Natarajan

Background: Diabetic Peripheral Neuropathy (DPN) is a debilitating complication of diabetes. Current diabetes management guidelines recommend targeting modifiable risk factors like glycemia, blood pressure (BP), lipids, obesity, and smoking to prevent DPN, but their individual effectiveness is unclear. Aim: To quantify the effectiveness of interventions targeting modifiable risk factors to prevent DPN in adults with Type 2 diabetes (T2D). Methods: The PubMed database was searched for randomized clinical trials (RCTs) from 1980 to 2023 focused on DPN prevention in adults with T2D. Eligible studies evaluated glycemic control, BP control, lipid control, obesity, or smoking cessation interventions against placebo or usual care, and reported DPN incidence for intervention and control groups. Meta-analysis for each therapy was conducted using a random-effects model in R. Heterogeneity was assessed using the I2 statistic. Results: Seven RCTs for glycemic control and three RCTs for BP control were identified for adults with T2D. There was no significant difference in the incidence of DPN between intervention and control groups for glycemic control (Odds Ratio [OR]=0.96, 95% Confidence Interval [CI] [0.88, 1.05], p=0.38, I2=0%) and BP control (OR=0.86, 95% CI [0.39, 1.88], p=0.70, I2=78%). We were unable to identify enough high-quality RCTs to conduct meta-analysis evaluating the effect of lipid control, smoking cessation, or obesity reduction on preventing DPN. Conclusions: While glycemic and BP control are recommended in clinical guidelines to prevent DPN, they have not been definitively shown to prevent incident DPN in adults with T2D. Identifying high-risk DPN groups using genomics or other markers and conducting high-quality RCTs in these high-risk groups using the aforementioned therapies calibrated to reach clearly specified risk factor levels may be needed to develop personalized treatments that are effective in preventing DPN in T2D. Disclosure S. Gunawan: None. T. Antony: None. A. Nicholson: None. S. Natarajan: None.

10.2337/db24-478-p

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Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-γ

Journal of Lipid Research (2000)

Jianwei Feng Jihong Han S. Freida A. Pearce Roy L. Silverstein Antonio M. Gotto

CD36, a class B scavenger receptor, is a macrophage receptor for oxidized low density lipoprotein (OxLDL) and may play a critical role in atherosclerotic foam cell formation. We have previously demonstrated that OxLDL, macrophage-colony stimulating factor (M-CSF), and interleukin-4 (IL-4) enhanced expression of CD36. The effect of OxLDL on CD36 is due, in part, to its ability to activate the transcription factor, PPAR-γ (peroxisome proliferator activated receptor-γ). Other PPAR-γ ligands (15-deoxyΔ12,14 prostaglandin J2 (15d-PGJ2) and the thiazolidinedione class of antidiabetic drugs) also increase CD36 expression. We have now evaluated signaling pathways involved in the induction of CD36. Treatment of RAW264.7 cells (a murine macrophage cell line) with protein kinase C (PKC) activators (diacylglycerol and ingenol) up-regulated CD36 mRNA expression. Specific inhibitors of PKC reduced CD36 expression in a time-dependent manner, while protein kinase A (PKA) and cyclic AMP agonists had no effect on CD36 mRNA expression. PKC inhibitors reduced basal expression of CD36 and blocked induction of CD36 mRNA by 15d-PGJ2, OxLDL and IL-4. In addition, PKC inhibitors decreased both PPAR-γ mRNA and protein expression and blocked induction of CD36 protein surface expression by OxLDL and 15d-PGJ2 in human monocytes, as determined by FACS. 15d-PGJ2 had no effect on translocation of PKC-α from the cytosol to the plasma membrane.These results demonstrate that two divergent physiological or pathophysiological agonists utilize a common pathway to up-regulate of CD36 gene expression. This pathway involves initial activation of PKC with subsequent PPAR-γ activation. Defining these signaling pathways is critical for understanding and modulating expression of this scavenger receptor pathway.—Feng, J., J. Han, S. F. A. Pearce, R. L. Silverstein, A. M. Gotto, Jr., D. P. Hajjar, and A. C. Nicholson. Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-γ. J. Lipid Res. 2000. 41: 688–696.

CD36

Scavenger Receptor

Troglitazone

10.1016/s0022-2275(20)32377-4

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Citations (240)

Cytokine regulation of low density lipoprotein receptor gene transcription in HepG2 cells

Journal of Biological Chemistry (1993)

Alison Stopeck Andrew Nicholson Francesco Paolo Mancini D P Hajjar

Elevated plasma levels of cytokines have been demonstrated in inflammatory, malignant, and infectious diseases.These disease states are often associated with abnormal lipid metabolism and reductions in plasma cholesterol levels.To determine if inflammatory cytokines could influence hepatic lipid metabolism, we evaluated low density lipoprotein (LDL) receptor function and gene expression in cytokine stimulated HepG2 cells, a hepatoblastoma-derived cell line which shares many functional similarities with normal hepatocytes.Tumor necrosis factor-a (TNF) and interleukin-18 (IL-1) increased LDL binding to HepG2 cells in a doseresponsive manner.Other cytokines including macrophage-colony stimulating factor, granulocyte macrophage-colony stimulating factor, and y-interferon had no significant effects on LDL binding.Increased binding in response to TNF or IL-1 was paralleled by increased steady-state levels of LDL receptor mRNA.Evaluation of LDL receptor mRNA half-life revealed no significant change in mRNA stability between control and TNF-or IL-1-stimulated cells.A fusion gene construct consisting of 1563 base pairs of the B'-flanking DNA of the human LDL receptor gene was coupled to a luciferase reporter gene, transfected into HepG2 cells, and promoter activity was assayed after TNF and IL-1 challenge to the cells.TNF and IL-1 increased promoter activity 200-400%, while treatment with LDL inhibited promoter activity by 70-85%.TNF or IL-1 co-incubation with LDL could not override transcriptional inhibition by LDL.Pretreatment with cycloheximide prevented induction of LDL receptor mRNA by TNF, but not by IL-1, suggesting stimulation of LDL receptor transcription by TNF requires protein synthesis.We propose that TNF and IL-1, acting via distinct signal transduction pathways, increase surface LDL receptors by increasing gene transcription.Our findings suggest that cytokine-induced hypocholesterolemia may be related to TNF and/or IL-1 stimulation of hepatic LDL receptor gene expression and function.The LDL' receptor is the primary receptor for binding and

LRP1B

Transcription

10.1016/s0021-9258(19)85360-7

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Citations (151)

Recombinant Glutathione S-Transferase/CD36 Fusion Proteins Define an Oxidized Low Density Lipoprotein-binding Domain

Journal of Biological Chemistry (1998)

S. Frieda A. Pearce Pampa Roy Andrew Nicholson David P. Hajjar Maria Febbraio

CD36 is a multifunctional cell-surface receptor that binds adhesion molecules such as thrombospondin-1 and collagen and modified lipids and/or lipoproteins. It participates in cellular uptake of photoreceptor outer segments and scavenging of apoptotic cells and oxidized low density lipoprotein (Ox-LDL). Recognition and internalization of Ox-LDL by mononuclear phagocytes may play an important role in the development of atherosclerotic lesions. We have utilized a series of recombinant bacterial glutathioneS-transferase/CD36 fusion proteins that span nearly all of the CD36 molecule to characterize the structural domain on CD36 that recognizes Ox-LDL. We found that the Ox-LDL-binding domain is different from the thrombospondin-1-binding domain located at amino acids 93–120. A fusion protein containing the region extending from amino acids 5 to 143 formed specific, saturable, and reversible complexes with Ox-LDL. As with intact CD36, binding was blocked by excess unlabeled Ox-LDL and antibodies to CD36. The stoichiometry and affinity of the fusion protein for Ox-LDL were similar to those of the intact protein. We also demonstrated that this fusion protein competitively inhibited binding of Ox-LDL to purified platelet CD36 and to CD36 expressed on peripheral blood monocytes and CD36 cDNA-transfected melanoma cells. The use of smaller peptides and fusion proteins including those spanning amino acids 28–93 and 5–93 has further narrowed the binding site to a region from amino acids 28 to 93, although participation of a sequence in the noncontiguous region 120–155 cannot be excluded. This study, for the first time, demonstrates unique regions of the scavenger receptor CD36 that bind the Ox-LDL ligand. Our structural analysis of the receptor provides information as to potential control of the trafficking of modified lipoproteins into the blood vessel wall.

Glutathione S-transferase

CD36

10.1074/jbc.273.52.34875

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Viral Induction of Endothelial Cell Procoagulant Activity

CRC Press eBooks (2024)

Andrew Nicholson David P. Hajjar

Hemostasis requires a balance between procoagulant activity, anticoagulant activity, fibrin assembly, and fibrinolysis. The vascular endothelium normally provides a thromboresistant surface. Perturbation of the endothelium by injury or activation in response to inflammatory mediators can shift this balance to one which promotes the assembly of the prothrombinase complex, thrombin generation and coagulation. In vitro experiments have shown that viral infection of vascular endothelial cells can inhibit anticoagulant function, induce the expression of receptors for coagulation proteins and thus, alter the balance of procoagulant and anticoagulant activity. In this review, we highlight data demonstrating that viral infection can directly (or indirectly via immune mechanisms) injure and activate the endothelium. In response, the endothelium can express receptors for coagulation proteins and inflammatory cells. We further speculate on how viral infection of the vascular endothelium and vessel wall may impact on the initiation and progression of atherosclerosis and summarize data implicating viral infection in this process.

Prothrombinase

10.1201/9781003580546-16

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Final FRCR 2B Long Cases: A Survival Guide

Academic Radiology (2012)

Andrew Nicholson

Oral examination

10.1016/j.acra.2011.07.024

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Depression as an etiologic and prognostic factor in coronary heart disease: a meta-analysis of 6608 events among 150<TS P>217 participants in 63 observational studies

European Journal of Cardiovascular Prevention & Rehabilitation (2006)

Andrew Nicholson Hannah Kuper Harry Hemingway

Depression

Coronary disease

10.1097/00149831-200605001-00073

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Genetic deletion of LDL receptor impairs mouse macrophage ABCA1 expression and cholesterol efflux: A new SREBP‐1 dependent mechanism

The FASEB Journal (2007)

Jihong Han Wei He Xiaoye Zhou Zhiping Huang Andrew Nicholson

LDLR mutations cause familial hypercholesterolemia and early atherosclerosis. Since ABCA1 facilitates free cholesterol efflux from peripheral tissues, we set out to investigate the effects of LDLR deletion (LDLR−/−) on macrophage ABCA1 expression and cholesterol efflux. LDLR−/− macrophages had reduced basal levels of ABCA1 and cholesterol efflux. High-fat diet increased cholesterol in LDLR−/− macrophages, but not in wild type cells. LXR agonist induced ABCA1 expression and cholesterol efflux in LDLR−/− macrophages, and modified lipoproteins induced ABCA1 expression in both cell types. Conversely, LDL induced ABCA1 expression in wild type but inhibited it in LDLR−/− macrophages, while free cholesterol stimulated ABCA1 expression in wild type but had no effect on LDLR−/− macrophages. 25-hydroxycholesterol inhibited SREBP-1 in wild type macrophages but activated it in LDLR−/− cells, and regulated ABCA1 expression differently in these two cell types. Inhibition of SREBP-1 by siRNA induced ABCA1 expression and cholesterol efflux. Taken together, our studies suggest that LDLR is critical in the regulation of macrophage cholesterol efflux and ABCA1 expression. We believe that absence of the LDLR suppresses ABCA1 expression and cholesterol efflux under condition of hypercholesterolemia. This may contribute to lipid accumulation in macrophages during the development of atherosclerosis.

Efflux

Foam cell

Liver X receptor

Reverse cholesterol transport

10.1096/fasebj.21.5.a16-c

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