Roy L Silverstein

Roy L Silverstein
Medical College of Wisconsin | MCW · Department of Medicine

MD

About

290
Publications
22,915
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
27,420
Citations
Citations since 2017
30 Research Items
7970 Citations
201720182019202020212022202302004006008001,0001,2001,400
201720182019202020212022202302004006008001,0001,2001,400
201720182019202020212022202302004006008001,0001,2001,400
201720182019202020212022202302004006008001,0001,2001,400
Introduction
Skills and Expertise

Publications

Publications (290)
Article
CD36 is a transmembrane glycoprotein receptor for oxidized low density lipoprotein (LDL) and other endogenous danger signals and promotes athero-thrombotic processes. CD36 has been shown to associate physically with other transmembrane proteins, including integrins, tetraspanins, and toll-like receptors, which modulate CD36-mediated cell signaling....
Article
Full-text available
Na/K-ATPase (NKA), besides its ion transporter function, is a signal transducer by regulating Src family kinases (SFK). The signaling NKA contributes to oxidized LDL-induced macrophage foam cell formation and interacts with TLR4. However, its role in LPS-induced signaling and glycolytic switch in macrophage remains unclear. Using peritoneal macroph...
Article
Full-text available
CD36 is a type 2 cell surface scavenger receptor widely expressed in many immune and non-immune cells. It functions as both a signaling receptor responding to DAMPs and PAMPs, as well as a long chain free fatty acid transporter. Recent studies have indicated that CD36 can integrate cell signaling and metabolic pathways through its dual functions an...
Article
Full-text available
Vimentin is a type III intermediate filament protein expressed in cells of mesenchymal origin. Vimentin has been thought to function mainly as a structural protein and roles of vimentin in other cellular processes have not been extensively studied. Our current study aims to reveal functions of vimentin in macrophage foam cell formation, the critica...
Article
The SARS-CoV-2 virus has infected hundreds of millions of people and caused millions of deaths worldwide. Reports of racial and ethnic disparities regarding both rates of infection of the SARS-CoV-2 virus and morbidity of the coronavirus disease-19 (COVID-19) contain profound differences depending on the population. A previous study found an indepe...
Article
Thrombotic and thromboembolic complications in patients diagnosed with coronavirus disease 2019 (COVID-19) are emerging as important sequelae that contribute to mortality, including disseminated intravascular coagulation, pulmonary embolism, deep vein thrombosis, ischemic stroke, and myocardial infraction. Reported incidence of thrombotic and throm...
Article
Full-text available
Epidemiologic studies in diabetic patients as well as research in model organisms have indicated the potential of metformin as a drug candidate for the treatment of various types of cancer, including breast cancer. To date most of the anti-cancer properties of metformin have, in large part, been attributed either to the inhibition of mitochondrial...
Article
Introduction and objective: A strong association between atherosclerosis and infections has been suggested in several studies. Clarifying the mechanism of macrophage inflammatory activation is critical to reduce the risk of atherosclerotic cardiovascular disease. Recent studies indicate that the Na/K-ATPase (NKA) is a novel regulator of macrophage...
Article
Background Alteration in blood triglyceride levels have been found in patients with coronavirus disease 2019 (COVID-19). However, the association between hypertriglyceridemia and mortality in COVID-19 patients is unknown. Objective To investigate the association between alteration in triglyceride level and mortality in hospitalized COVID-19 patien...
Article
1. Developing and implementing an intensive interdisciplinary medical home within a large academic medical center was feasible. 2. Deploying a complex care management program that shared staff and resources with an intensive primary care program was not successful. 3. Barriers included traversing legal barriers to text messaging patients, making ho...
Article
Full-text available
Arterial thrombosis in the setting of dyslipidemia promotes clinically significant events, including myocardial infarction and stroke. Oxidized lipids in low-density lipoproteins (oxLDL) are a risk factor for athero-thrombosis and are recognized by platelet scavenger receptor CD36. oxLDL binding to CD36 promotes platelet activation and thrombosis b...
Article
While increased levels of high density lipoprotein (HDL)‐cholesterol correlate with protection against cardiovascular disease, recent findings demonstrate that HDL function, rather than HDL‐cholesterol levels, may be a better indicator of cardiovascular risk. One mechanism by which HDL function can be compromised is through modification by reactive...
Article
Arterial thrombosis in the setting of dyslipidemia produces clinically significant events, including myocardial infarction and stroke. Oxidized lipids in circulating lipoproteins (oxLDL) are a risk factor for atherothrombosis in dyslipidemia and are recognized by platelet scavenger receptor CD36. OxLDL binding to CD36 promotes platelet activation a...
Article
Rationale: A hallmark of chronic inflammatory disorders is persistence of proinflammatory macrophages in diseased tissues. In atherosclerosis, this is associated with dyslipidemia and oxidative stress, but mechanisms linking these phenomena to macrophage activation remain incompletely understood. Objective: To investigate mechanisms linking dysl...
Article
Purpose of review: Metabolic diseases, including dyslipidemia, diabetes mellitus, and chronic inflammation are risk factors for clinically significant thrombotic events. Thrombosis in these settings is multifaceted with coordinated mechanisms between platelet activation and the hemostatic pathways. This review focuses on recent advances in platele...
Article
Thrombocytopenia is associated with worse outcomes in patients with acute respiratory distress syndrome, which is most commonly caused by infection and marked by alveolar-capillary barrier disruption. However, the mechanisms by which platelets protect the lung alveolar-capillary barrier during infectious injury remain unclear. We found that nativel...
Article
Scavenger receptor CD36 is a multifunctional membrane protein that promotes thrombosis in conditions of oxidative stress such as metabolic disorders including dyslipidemia, diabetes mellitus, and chronic inflammation. In these conditions, specific reactive oxidant species are generated that are context and cell dependent. In the vasculature, CD36 s...
Article
Objective— Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results— We found by immun...
Article
Thrombosis during atherosclerotic plaque erosion or rupture is a major cause of death and disability in individuals with cardiovascular disease. Circulating oxidized lipids are risk factors for this condition and are carried in oxidized low-density lipoprotein particles (oxLDL). CD36 is a pattern recognition receptor that recognizes oxLDL and conse...
Article
Dyslipidemia is a risk factor for clinically significant thrombotic events. In this condition, scavenger receptor CD36 potentiates platelet reactivity through recognition of circulating oxidized lipids. CD36 promotes thrombosis by activating redox-sensitive signaling molecules, such as the MAPK extracellular signal-regulated kinase 5 (ERK5). Howeve...
Article
Metabolic pathways intersect with many processes important in hematology, including thrombosis, innate and adaptive immunity, malignant transformation, and stem cell function. These pathways are increasingly recognized as potentially targetable for therapeutic intervention. In this issue of Blood, Lepropre et al identify the energy sensor AMP-activ...
Article
Objective: Circulating levels of cardiotonic steroids (CTS) are elevated in various chronic inflammatory conditions, but the role of CTS in inflammation remains largely unknown. We have previously shown that the CTS ouabain stimulates proinflammatory responses in murine macrophages. In this study, we aim to explore the mechanism how CTS induce pro...
Article
The role of high density lipoproteins (HDL) in protecting against cardiovascular disease is compromised when HDL undergoes modification during conditions of oxidative stress; however, the mechanisms underlying these changes in HDL function are not well defined. Reactive aldehydes such as acrolein (a major component in cigarette smoke) or major prod...
Article
Key Points Atherogenic conditions promote platelet CD36 signaling by generating specific reactive oxygen species. Redox sensor ERK5 MAP kinase activation by reactive oxygen species potentiates thrombus formation in hyperlipidemic conditions.
Article
Full-text available
Obesity increases cancer risk including breast cancer (BC). However, the direct regulatory mechanisms by which obesity promotes BC progression remain largely unknown. We show that lysophosphatidic acid/protein kinase D1 (LPA/PKD-1)-CD36 signaling is a bona fide breast cancer promoter via stimulating microvascular remodeling in chronic diet-induced...
Article
Atherosclerotic plaque instability is a pathological process that can lead to ischemic emergencies, such as myocardial infarction (MI) and stroke. Thrombosis in this context is promoted by circulating oxidized lipids present in LDL particles (oxLDL), which are generated during plaque formation. These particles are recognized by scavenger receptor C...
Article
Antiplatelet therapeutics are a mainstay of primary and secondary prevention strategies for thrombotic cardiovascular and neurovascular diseases. Currently available agents, aspirin and thienopyridines, directly target platelet activation pathways mediated by thromboxane A2 (the major metabolic product of platelet cyclooxygenase) and ADP. These cri...
Article
Protein Z (PZ) is a vitamin K-dependent plasma protein that exhibits both pro- and anticoagulant properties. Both low and high PZ levels have been linked to ischaemic stroke. Although PZ-lowering gene variants have been found to be less common in ischaemic stroke, the relationship remains unclear. We investigated PZ levels and PROZ variants in a mu...
Article
Klebsiella pneumoniae remains an important cause of intrapulmonary infection and invasive disease worldwide. Klebsiella pneumoniae can evade serum killing and phagocytosis primarily through the expression of a polysaccharide capsule, but its pathogenicity is also influenced by host factors. We examined whether CD36, a scavenger receptor that recogn...
Article
High density lipoproteins (HDL) are athero-protective particles that promote the removal of excess cholesterol from lipid-loaded macrophages and stimulate their migration in order to protect against foam cell formation, a precursor to atherosclerotic plaque build-up. Recently, studies have shown that oxidative modification of HDL prevents HDL from...
Article
Objective: CD36 is a scavenger and antiangiogenic receptor that is important in atherothrombotic diseases, diabetes mellitus, cancer, and obesity. Lysophosphatidic acid, a phospholipid signaling mediator, abolishes endothelial cell responses to antiangiogenic proteins containing thrombospondin type 1 homology domains by downregulating endothelial...
Article
Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyp...
Article
Objective: Literature on the effect of cell-derived extracellular vesicles (EV), ≤1 μm vesicles shed from various cell types during activation or apoptosis, on microvascular endothelial cell (MVEC) signaling is conflicting. Thrombospondin-1 and related proteins induce anti-angiogenic signals in MVEC via CD36. CD36 binds EV via phosphatidylserine e...
Article
Atherothrombosis is a pathological event initiated by dysregulated platelet activation in the setting of unstable or ruptured atherosclerotic plaque, leading to myocardial infarction or stroke. Platelets express scavenger receptor CD36, a receptor of the innate immune system that recognizes endogenous danger signals, such as oxidized low-density li...
Article
The initiation, progression, and complications of atherosclerosis are mediated by a complex interplay of hematopoietic cells, vascular cells, and the extracellular matrix in response to metabolic (e.g., hyperlipidemia, diabetes mellitus) and environmental (e.g., smoking) injury(1). Recruitment and activation of immune cells of hematopoietic origin...
Article
Full-text available
One characteristic of atherosclerosis is the accumulation of lipid-laden macrophage foam cells in the arterial wall. We have previously shown that the binding of oxidized low-density lipoprotein (oxLDL) to the scavenger receptor CD36 activates the kinase Lyn, initiating a cascade that inhibits macrophage migration and is necessary for foam cell gen...
Article
This Podcast features an interview with Roy L. Silverstein, author of a Research Article that appears in the 8 September 2015 issue of Science Signaling, about signaling events in macrophages the lead to the formation of the foam cells that are associated with atherosclerotic plaques. Under certain conditions, low-density lipoproteins (LDL) penetra...
Article
Cardiotonic steroids such as ouabain, digoxin, and marinobufagenin are known ligands for the plasma membrane receptor Na/K-ATPase (NKA). These ligands are able to stimulate interaction of the NKA with other membrane and cytosolic proteins leading to cellular events such as activation of kinase cascades and gene transcription. Endogenous cardiotonic...
Article
Background: CD36 is a scavenger and antiangiogenic receptor that plays an important role in athero-thrombotic diseases, diabetes and cancer and contributes to obesity. Lysophosphatidic acid (LPA), a bioactive phospholipid signaling mediator, abolishes endothelial cell responses to antiangiogenic proteins containing thrombospondin type 1 homology do...
Article
In this issue of Blood, Magwenzi et al from the University of Hull report a novel mechanistic connection between oxidized low-density lipoprotein (oxLDL)-induced prothrombotic platelet signaling and the inhibition of endogenous platelet anti-activating signaling mediated by the nitric oxide (NO)/guanosine 3′,5′-cyclic monophosphate (cGMP)/protein k...
Article
Full-text available
High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundanc...
Article
The objective of this study is to assess the relationship between inflammatory disease in granulomatosis with polyangiitis (GPA, Wegener's) and the development of subclinical atherosclerosis. A total of 46 adult patients with GPA were enrolled. Disease status was measured by Birmingham vasculitis assessment scores as modified for GPA, vasculitis da...
Article
Full-text available
Neutrophil elastase (NE) and cathepsin G (CG) contribute to intracellular microbial killing but, if left unchecked and released extracellularly, promote tissue damage. Conversely, mechanisms that constrain neutrophil serine protease activity protect against tissue damage but may have the untoward effect of disabling the microbial killing arsenal. T...
Article
Rationale: Platelets contain abundant thymidine phosphorylase (TYMP), which is highly expressed in diseases with high risk of thrombosis, such as atherosclerosis and type II diabetes mellitus. Objective: To test the hypothesis that TYMP participates in platelet signaling and promotes thrombosis. Methods and results: By using a ferric chloride...
Article
Full-text available
Injury initiates recruitment of macrophages to support tissue repair however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the PPAR-γ agonist, rosiglitazone (Rosi), a medication recently re-introduced as a drug to treat diabetes and with known anti-inf...
Article
IntroductionActivated platelets shed microparticles from plasma membranes, but also release smaller exosomes from internal compartments. While microparticles participate in athero-thrombosis, little is known of exosomes in this process. Materials & Methods Ex vivo biochemical experiments with human platelets and exosomes, and FeCl3-induced murine c...
Article
Glioblastoma (GBM) contains a self-renewing, tumorigenic cancer stem cell (CSC) population which contributes to tumor propagation and therapeutic resistance. While the tumor microenvironment is essential to CSC self-renewal, the mechanisms by which CSCs sense and respond to microenvironmental conditions are poorly understood. Scavenger receptors ar...
Article
Platelet secretion in response to agonist stimulation is a critically important step in both normal hemostasis and pathological arterial thrombosis. ADP release from dense granules is necessary to convert a low-grade, often reversible platelet activation event into an irreversible event, and targeting this pathway pharmacologically by inhibiting cy...
Article
Lysophosphatidic acid (LPA), a bioactive signaling phospholipid, down-regulates CD36 expression in microvascular endothelial cells (MVECs) via protein kinase PKD-1 signaling, thereby abolishing endothelial cell responses to its antiangiogenic ligand thrombospondin-1. However, little is known regarding mechanisms by which MVEC-specific CD36 transcri...
Article
Cell-derived microparticles (MP), ≤1μm vesicles shed from vascular and blood cells during activation or apoptosis, circulate in plasma and are biomarkers of cardiovascular disease. The type 2 scavenger receptor CD36 binds MP via phosphatidylserine exposed on their surface. On microvascular endothelial cells (MVEC) CD36 induces anti-angiogenic signa...
Article
CD36 is a transmembrane glycoprotein belonging to the type 2 scavenger receptor family. On macrophages and platelets CD36 recognizes oxidized LDL and other endogenous danger signals and thereby transmits signals that promote athero-thrombotic processes. CD36 has been shown to associate physically with other transmembrane proteins, including integri...
Article
Full-text available
Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been estab...
Article
Full-text available
Proteasome inhibitors used in the treatment of hematologic cancers also reduce thrombosis. Whether the proteasome participates in platelet activation or function is unclear because little is known of the proteasome in these terminally differentiated cells. Platelets displayed all 3 primary proteasome protease activities, which MG132 and bortezomib...
Article
Full-text available
LPS activates platelets through TLR4, aiding productive sepsis, with stimulated splicing and translation of stored heteronuclear pro-IL-1β RNA. Although the IL-1R type 1 (IL-1R1) receptor for IL-1 shares downstream components with the TLR4 receptor, platelets are not known to express IL-1R1, nor are they known to respond to this cytokine. We show b...
Article
Full-text available
Mononuclear phagocyte recognition of apoptotic cells triggering suppressive cytokine signaling is a key event in inflammation resolution from injury. Mice deficient in thrombospondin (TSP)-1 (thbs1(-/-)), an extracellular matrix glycoprotein that bridges cell-cell interactions, are prone to lipopolysaccharide-induced lung injury and show defective...
Article
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC CD36 is an endothelial cell (EC) receptor that mediates angiostatic activity and oxidative stress, which are important in ischemic disease and tumor progression. CD36 interacts with TSR domain proteins including thrombospondin-1. This results in a signal that is likely to...
Article
Full-text available
Key Points TSP-1 binding to CD36 recruits SHP-1 to CD36-VEGFR2 complex in microvascular endothelial cells. SHP-1 recruitment to CD36-VEGFR2 complex dephosphorylates VEGFR2 and inhibits angiogenesis.
Article
Atherosclerosis requires migration of monocytes to the arterial intima, with subsequent differentiation into foam cells. We showed previously that the scavenger receptor CD36 contributes to the activation of Vav family guanine nucleotide exchange factors (Vavs) in aortae from hyperlipidemic apoE-null mice and that oxidatively modified low-density l...
Article
Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxLDL uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range...
Article
Objective: Antiangiogenic activity of thrombospondin-1 and related proteins is mediated by interactions between thrombospondin type 1 repeat (TSR) domains and the CD36, LIMP-2, Emp sequence homology (CLESH) domain of the endothelial cell receptor CD36. We sought to characterize key molecular determinants of the interaction between thrombospondin-1...
Article
Full-text available
Ferric chloride (FeCl3) induced vascular injury is a widely used model of occlusive thrombosis that reports platelet activation in the context of an aseptic closed vascular system. This model is based on redox-induced endothelial cell injury, which is simple and sensitive to both anticoagulant and anti-platelets drugs. The time required for platele...
Article
Full-text available
Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular...
Article
Full-text available
Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ∼2100 metabolic and cardiovascular-related loci to genotype up t...
Article
Proatherogenic, hyperlipidemic states demonstrate increases in circulating ligands for scavenger receptor CD36 (eg, oxidized low-density lipoprotein [oxLDL]) and the Na/K-ATPase (eg, cardiotonic steroids). These factors increase inflammation, oxidative stress, and progression of chronic kidney disease. We hypothesized that diet-induced obesity and...
Article
Full-text available
Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identif...
Article
Full-text available
The angiogenic switch is a promising therapeutic target in cancer. Work by our laboratory and others has described an important endogenous anti-angiogenic pathway mediated by interactions of CD36, a receptor on microvascular endothelial cells, with proteins containing thrombospondin (TSP) type I repeat domains (TSR). Recent studies revealed that ci...