Publications by authors named "Kathryn J Moore"

126 Publications

High-Throughput Screening Identifies MicroRNAs Regulating Human PCSK9 and Hepatic Low-Density Lipoprotein Receptor Expression.

Front Cardiovasc Med 2021 12;8:667298. Epub 2021 Jul 12.

Leon H. Charney Division of Cardiology, Department of Medicine, New York University Cardiovascular Research Center, New York University School of Medicine, New York, NY, United States.

Investigations into the regulatory mechanisms controlling cholesterol homeostasis have proven fruitful in identifying low-density lipoprotein (LDL)-lowering therapies to reduce the risk of atherosclerotic cardiovascular disease. A major advance was the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a secreted protein that binds the LDL receptor (LDLR) on the cell surface and internalizes it for degradation, thereby blunting its ability to take up circulating LDL. The discovery that loss-of-function mutations in lead to lower plasma levels of LDL cholesterol and protection from cardiovascular disease led to the therapeutic development of PCSK9 inhibitors at an unprecedented pace. However, there remain many gaps in our understanding of PCSK9 regulation and biology, including its posttranscriptional control by microRNAs. Using a high-throughput region(3'-UTR) of human microRNA library screen, we identified microRNAs targeting the 3' untranslated region of human PCSK9. The top 35 hits were confirmed by large-format PCSK9 3'-UTR luciferase assays, and 10 microRNAs were then selected for further validation in hepatic cells, including effects on PCSK9 secretion and LDLR cell surface expression. These studies identified seven novel microRNAs that reduce PCSK9 expression, including miR-221-5p, miR-342-5p, miR-363-5p, miR-609, miR-765, and miR-3165. Interestingly, several of these microRNAs were also found to target other genes involved in LDLR regulation and potently upregulate LDLR cell surface expression in hepatic cells. Together, these data enhance our understanding of post-transcriptional regulators of PCSK9 and their potential for therapeutic manipulation of hepatic LDLR expression.
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http://dx.doi.org/10.3389/fcvm.2021.667298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310920PMC
July 2021

Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression.

Circ Res 2021 Jul 22. Epub 2021 Jul 22.

Cardiology, New York University Langone Medical Center, UNITED STATES.

Therapeutic efforts to decrease atherosclerotic cardiovascular disease risk have focused largely on reducing atherogenic lipoproteins, yet lipid lowering therapies alone are insufficient to fully regress plaque burden. We postulate that arterial repair requires resolution of a maladaptive immune response, and that targeting factors that hinder inflammation resolution will facilitate plaque regression. The guidance molecule netrin-1 is secreted by macrophages in atherosclerotic plaques, where it sustains inflammation by enhancing macrophage survival and blocking macrophage emigration. We tested whether silencing netrin-1 in advanced atherosclerosis could resolve arterial inflammation and regress plaques. To temporally silence netrin-1 in myeloid cells, we generated genetically modified mice in which Ntn1 could be selectively deleted in monocytes and macrophages using a tamoxifen-induced CX3CR1-driven cre-recombinase () and littermate control mice (). Mice were fed western diet in the setting of hepatic PCSK9 overexpression to render them atherosclerotic, and then treated with tamoxifen to initiate deletion of myeloid netrin-1 (Mø) or not in controls (Mø). Morphometric analyses performed 4 weeks later showed that myeloid Ntn1 silencing reduced plaque burden in the aorta (-50%) and plaque complexity in the aortic root. Monocyte-macrophage tracing experiments revealed lower monocyte recruitment, macrophage retention, and proliferation in Mø compared to Mø plaques, indicating a restructuring of monocyte-macrophage dynamics in the artery wall upon netrin-1 silencing. Single cell RNA-sequencing of aortic immune cells prior to and after netrin-1 silencing revealed upregulation of gene pathways involved in macrophage phagocytosis and migration, including the Ccr7 chemokine receptor signaling pathway required for macrophage emigration from plaques and atherosclerosis regression. Additionally, plaques from Mø mice showed hallmarks of inflammation resolution, including higher levels of pro-resolving macrophages, interleukin-10, and efferocytosis, as compared to plaques from Mø mice. Our data show that targeting netrin-1 in advanced atherosclerosis ameliorates atherosclerotic inflammation and promotes plaque regression.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319313DOI Listing
July 2021

MicroRNA-33 Inhibits Adaptive Thermogenesis and Adipose Tissue Beiging.

Arterioscler Thromb Vasc Biol 2021 04 4;41(4):1360-1373. Epub 2021 Mar 4.

NYU Cardiovascular Research Center (M.S.A., C.v.S., Y.C., M. Sharma, E.M.C., M. Schlegel, L.C.S., D.P., J.Y.Y., K.J.M.), New York University School of Medicine.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.120.315798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011606PMC
April 2021

miR-33 Silencing Reprograms the Immune Cell Landscape in Atherosclerotic Plaques.

Circ Res 2021 Apr 17;128(8):1122-1138. Epub 2021 Feb 17.

Department of Medicine, Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine (M.S.A., M. Sharma, M. Schlegel, C.v.S., G.J.K., L.C.S., L.B., D.P., K.R., E.J.B., E.A.F., K.J.M.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049965PMC
April 2021

Crosstalk Between the Heart and Cancer: Beyond Drug Toxicity.

Circulation 2020 Aug 17;142(7):684-687. Epub 2020 Aug 17.

Department of Medicine, Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, NY (K.L.M.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436939PMC
August 2020

COVID-19 and the Heart and Vasculature: Novel Approaches to Reduce Virus-Induced Inflammation in Patients With Cardiovascular Disease.

Arterioscler Thromb Vasc Biol 2020 09 20;40(9):2045-2053. Epub 2020 Jul 20.

From the Department of Medicine, Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine (B.S.K., M.S.G., K.J.M., J.D.N., R.R., H.R.R., J.H., G.I.F., S.D.K.).

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented challenge and opportunity for translational investigators to rapidly develop safe and effective therapeutic interventions. Greater risk of severe disease in COVID-19 patients with comorbid diabetes mellitus, obesity, and heart disease may be attributable to synergistic activation of vascular inflammation pathways associated with both COVID-19 and cardiometabolic disease. This mechanistic link provides a scientific framework for translational studies of drugs developed for treatment of cardiometabolic disease as novel therapeutic interventions to mitigate inflammation and improve outcomes in patients with COVID-19.
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http://dx.doi.org/10.1161/ATVBAHA.120.314513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446967PMC
September 2020

Myocardial infarction accelerates breast cancer via innate immune reprogramming.

Nat Med 2020 09 13;26(9):1452-1458. Epub 2020 Jul 13.

NYU Cardiovascular Research Center, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA.

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity or surgery, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6C monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6C monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.
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http://dx.doi.org/10.1038/s41591-020-0964-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789095PMC
September 2020

LDL Receptor Pathway Regulation by miR-224 and miR-520d.

Front Cardiovasc Med 2020 22;7:81. Epub 2020 May 22.

Leon H. Charney Division of Cardiology, NYU Cardiovascular Research Center, Department of Medicine, New York University School of Medicine, New York, NY, United States.

MicroRNAs (miRNA) have emerged as important post-transcriptional regulators of metabolic pathways that contribute to cellular and systemic lipoprotein homeostasis. Here, we identify two conserved miRNAs, miR-224, and miR-520d, which target gene networks regulating hepatic expression of the low-density lipoprotein (LDL) receptor (LDLR) and LDL clearance. prediction of miR-224 and miR-520d target gene networks showed that they each repress multiple genes impacting the expression of the LDLR, including the chaperone molecules PCSK9 and IDOL that limit LDLR expression at the cell surface and the rate-limiting enzyme for cholesterol synthesis HMGCR, which is the target of LDL-lowering statin drugs. Using gain- and loss-of-function studies, we tested the role of miR-224 and miR-520d in the regulation of those predicted targets and their impact on LDLR expression. We show that overexpression of miR-224 or miR-520d dose-dependently reduced the activity of , and 3'-untranslated region (3'-UTR)-luciferase reporter constructs and that this repression was abrogated by mutation of the putative miR-224 or miR-520d response elements in the , and 3'-UTRs. Compared to a control miRNA, overexpression of miR-224 or miR-520d in hepatocytes inhibited , and mRNA and protein levels and decreased PCSK9 secretion. Furthermore, miR-224 and miR-520d repression of , and was associated with an increase in LDLR protein levels and cell surface expression, as well as enhanced LDL binding. Notably, the effects of miR-224 and miR-520d were additive to the effects of statins in upregulating LDLR expression. Finally, we show that overexpression of miR-224 in the livers of mice using lipid nanoparticle-mediated delivery resulted in a 15% decrease in plasma levels of LDL cholesterol, compared to a control miRNA. Together, these findings identify roles for miR-224 and miR-520d in the posttranscriptional control of LDLR expression and function.
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http://dx.doi.org/10.3389/fcvm.2020.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256473PMC
May 2020

An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation.

Circ Res 2020 05 21;126(11):1565-1589. Epub 2020 May 21.

From the Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (L.A., H.H.R., R.A.W., M.B.M., P.F.G., R.R., A.M.S.), NYU Grossman School of Medicine, New York.

The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow-derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type-specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250004PMC
May 2020

Introduction to the Obesity, Metabolic Syndrome, and CVD Compendium.

Circ Res 2020 05 21;126(11):1475-1476. Epub 2020 May 21.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (R.S.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250157PMC
May 2020

Leukocyte Heterogeneity in Adipose Tissue, Including in Obesity.

Circ Res 2020 05 21;126(11):1590-1612. Epub 2020 May 21.

From the Cardiovascular Research Center, Leon H. Charney Division of Cardiology, Department of Medicine (A.W., K.J.M., E.A.F.), New York University Grossman School of Medicine.

Adipose tissue (AT) plays a central role in both metabolic health and pathophysiology. Its expansion in obesity results in increased mortality and morbidity, with contributions to cardiovascular disease, diabetes mellitus, fatty liver disease, and cancer. Obesity prevalence is at an all-time high and is projected to be 50% in the United States by 2030. AT is home to a large variety of immune cells, which are critical to maintain normal tissue functions. For example, γδ T cells are fundamental for AT innervation and thermogenesis, and macrophages are required for recycling of lipids released by adipocytes. The expansion of visceral white AT promotes dysregulation of its immune cell composition and likely promotes low-grade chronic inflammation, which has been proposed to be the underlying cause for the complications of obesity. Interestingly, weight loss after obesity alters the AT immune compartment, which may account for the decreased risk of developing these complications. Recent technological advancements that allow molecular investigation on a single-cell level have led to the discovery of previously unappreciated heterogeneity in many organs and tissues. In this review, we will explore the heterogeneity of immune cells within the visceral white AT and their contributions to homeostasis and pathology.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250138PMC
May 2020

Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression.

Circ Res 2020 07 27;127(3):335-353. Epub 2020 Apr 27.

From the Leon H. Charney Division of Cardiology, Department of Medicine (M. Sharma, M.P.S., M.S.A., E.J.B., K.R., A.W., E.M.C., C.v.S., G.J.K., L.C.S., L.B., D.P., E.A.F., K.J.M.), New York University Grossman School of Medicine.

Rationale: Regression of atherosclerosis is an important clinical goal; however, the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, yet the numbers of these immunosuppressive cells decrease with disease progression, and whether they contribute to atherosclerosis regression is not known.

Objective: We investigated the roles of Tregs in the resolution of atherosclerotic inflammation, tissue remodeling, and plaque contraction during atherosclerosis regression.

Methods And Results: Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. Single-cell RNA-sequencing of plaque immune cells revealed that unlike Tregs from progressing plaques that expressed markers of natural Tregs derived from the thymus, Tregs in regressing plaques lacked expression, suggesting that they are induced in the periphery during lipid-lowering therapy. To test whether Tregs are required for resolution of atherosclerotic inflammation and plaque regression, Tregs were depleted using CD25 monoclonal antibody in atherosclerotic mice during apolipoprotein B antisense oligonucleotide-mediated lipid lowering. Morphometric analyses revealed that Treg depletion blocked plaque remodeling and contraction, and impaired hallmarks of inflammation resolution, including dampening of the T helper 1 response, alternative activation of macrophages, efferocytosis, and upregulation of specialized proresolving lipid mediators.

Conclusions: Our data establish essential roles for Tregs in resolving atherosclerotic cardiovascular disease and provide mechanistic insight into the pathways governing plaque remodeling and regression of disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367765PMC
July 2020

A heritable netrin-1 mutation increases atherogenic immune responses.

Atherosclerosis 2020 05 10;301:82-83. Epub 2020 Apr 10.

NYU Cardiovascular Research Center, The Leon H. Charney Division of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769589PMC
May 2020

Enhanced glycolysis and HIF-1α activation in adipose tissue macrophages sustains local and systemic interleukin-1β production in obesity.

Sci Rep 2020 03 27;10(1):5555. Epub 2020 Mar 27.

Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University Langone Health, New York, NY, USA.

During obesity, macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type II diabetes. Evidence suggests that the rewiring of cellular metabolism can regulate macrophage function. However, the metabolic programs that characterize adipose tissue macrophages (ATM) in obesity are poorly defined. Here, we demonstrate that ATM from obese mice exhibit metabolic profiles characterized by elevated glycolysis and oxidative phosphorylation, distinct from ATM from lean mice. Increased activation of HIF-1α in ATM of obese visceral adipose tissue resulted in induction of IL-1β and genes in the glycolytic pathway. Using a hypoxia-tracer, we show that HIF-1α nuclear translocation occurred both in hypoxic and non-hypoxic ATM suggesting that both hypoxic and pseudohypoxic stimuli activate HIF-1α and its target genes in ATM during diet-induced obesity. Exposure of macrophages to the saturated fatty acid palmitate increased glycolysis and HIF-1α expression, which culminated in IL-1β induction thereby simulating pseudohypoxia. Using mice with macrophage-specific targeted deletion of HIF-1α, we demonstrate the critical role of HIF-1α-derived from macrophages in regulating ATM accumulation, and local and systemic IL-1β production, but not in modulating systemic metabolic responses. Collectively, our data identify enhanced glycolysis and HIF-1α activation as drivers of low-grade inflammation in obesity.
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http://dx.doi.org/10.1038/s41598-020-62272-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101445PMC
March 2020

Mycobacterium tuberculosis Limits Host Glycolysis and IL-1β by Restriction of PFK-M via MicroRNA-21.

Cell Rep 2020 01;30(1):124-136.e4

School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland; Conway Institute, University College Dublin, Dublin, Ireland. Electronic address:

Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1β (IL-1β). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function.
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http://dx.doi.org/10.1016/j.celrep.2019.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764301PMC
January 2020

Connecting Transcriptional and Functional Macrophage Heterogeneity in Atherosclerosis.

Circ Res 2019 12 5;125(12):1052-1054. Epub 2019 Dec 5.

From the Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine.

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http://dx.doi.org/10.1161/CIRCRESAHA.119.316168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951245PMC
December 2019

Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis.

Sci Transl Med 2019 11;11(517)

Marc and Ruti Bell Program in Vascular Biology, Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.

Platelets are best known as mediators of hemostasis and thrombosis; however, their inflammatory effector properties are increasingly recognized. Atherosclerosis, a chronic vascular inflammatory disease, represents the interplay between lipid deposition in the artery wall and unresolved inflammation. Here, we reveal that platelets induce monocyte migration and recruitment into atherosclerotic plaques, resulting in plaque platelet-macrophage aggregates. In mice fed a Western diet, platelet depletion decreased plaque size and necrotic area and attenuated macrophage accumulation. Platelets drive atherogenesis by skewing plaque macrophages to an inflammatory phenotype, increasing myeloid suppressor of cytokine signaling 3 (SOCS3) expression and reducing the ratio. Platelet-induced expression regulates plaque macrophage reprogramming by promoting inflammatory cytokine production (, , and ) and impairing phagocytic capacity, dysfunctions that contribute to unresolved inflammation and sustained plaque growth. Translating our data to humans with cardiovascular disease, we found that women with, versus without, myocardial infarction have up-regulation of , lower , and increased monocyte-platelet aggregate. A second cohort of patients with lower extremity atherosclerosis demonstrated that and the ratio correlated with platelet activity and inflammation. Collectively, these data provide a causative link between platelet-mediated myeloid inflammation and dysfunction, , and cardiovascular disease. Our findings define an atherogenic role of platelets and highlight how, in the absence of thrombosis, platelets contribute to inflammation.
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http://dx.doi.org/10.1126/scitranslmed.aax0481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905432PMC
November 2019

Netrin-1 Alters Adipose Tissue Macrophage Fate and Function in Obesity.

Immunometabolism 2019 7;1(2). Epub 2019 Aug 7.

Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.

Macrophages accumulate prominently in the visceral adipose tissue (VAT) of obese humans and high fat diet (HFD) fed mice, and this is linked to insulin resistance and type II diabetes. While the mechanisms regulating macrophage recruitment in obesity have been delineated, the signals directing macrophage persistence in VAT are poorly understood. We previously showed that the neuroimmune guidance cue netrin-1 is expressed in the VAT of obese mice and humans, where it promotes macrophage accumulation. To better understand the source of netrin-1 and its effects on adipose tissue macrophage (ATM) fate and function in obesity, we generated mice with myeloid-specific deletion of netrin-1 ( ; Ntn1). Interestingly, Ntn1 mice showed a modest decrease in HFD-induced adiposity and adipocyte size, in the absence of changes in food intake or leptin, that was accompanied by an increase in markers of adipocyte beiging (, UCP-1). Using single cell RNA-seq, combined with conventional histological and flow cytometry techniques, we show that myeloid-specific deletion of netrin-1 caused a 50% attrition of ATMs in HFD-fed mice, particularly of the resident macrophage subset, and altered the phenotype of residual ATMs to enhance lipid handling. Pseudotime analysis of single cell transcriptomes showed that in the absence of netrin-1, macrophages in the obese VAT underwent a phenotypic switch with the majority of ATMs activating a program of genes specialized in lipid handling, including fatty acid uptake and intracellular transport, lipid droplet formation and lipolysis, and regulation of lipid localization. Furthermore, Ntn1 macrophages had reduced expression of genes involved in arachidonic acid metabolism, and targeted LCMS/MS metabololipidomics analysis revealed decreases in proinflammatory eicosanoids (5-HETE, 6- LTB, TXB, PGD) in the obese VAT. Collectively, our data show that targeted deletion of netrin-1 in macrophages reprograms the ATM phenotype in obesity, leading to reduced adipose inflammation, and improved lipid handling and metabolic function.
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http://dx.doi.org/10.20900/immunometab20190010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699780PMC
August 2019

The long noncoding RNA CHROME regulates cholesterol homeostasis in primate.

Nat Metab 2019 01 3;1(1):98-110. Epub 2018 Dec 3.

Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.

The human genome encodes thousands of long non-coding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (), elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, that regulates cellular and systemic cholesterol homeostasis. LncRNA expression is influenced by dietary and cellular cholesterol via the sterol-activated liver X receptor transcription factors, which control genes mediating responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that promotes cholesterol efflux and HDL biogenesis by curbing the actions of a set of functionally related microRNAs that repress genes in those pathways. knockdown in human hepatocytes and macrophages increases levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing expression of their overlapping target gene networks and associated biologic functions. In particular, cells lacking show reduced expression of ABCA1, which regulates cholesterol efflux and nascent HDL particle formation. Collectively, our findings identify as a central component of the non-coding RNA circuitry controlling cholesterol homeostasis in humans.
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http://dx.doi.org/10.1038/s42255-018-0004-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691505PMC
January 2019

Single-Cell RNA Sequencing of Visceral Adipose Tissue Leukocytes Reveals that Caloric Restriction Following Obesity Promotes the Accumulation of a Distinct Macrophage Population with Features of Phagocytic Cells.

Immunometabolism 2019 19;1. Epub 2019 Jul 19.

Department of Medicine, Division of Cardiology, Marc and Ruti Bell Program in Vascular Biology, NYU School of Medicine, New York, NY 10016, USA.

Obesity can lead to type 2 diabetes and is an epidemic. A major contributor to its adverse effects is inflammation of the visceral adipose tissue (VAT). Life-long caloric restriction (CR), in contrast, results in extended lifespan, enhanced glucose tolerance/insulin sensitivity, and other favorable phenotypes. The effects of CR following obesity are incompletely established, but studies show multiple benefits. Many leukocyte types, macrophages predominantly, reside in VAT in homeostatic and pathological states. CR following obesity transiently increases VAT macrophage content prior to resolution of inflammation and obesity, suggesting that macrophage content and phenotype play critical roles. Here, we examined the heterogeneity of VAT leukocytes and the effects of obesity and CR. In general, our single-cell RNA-sequencing data demonstrate that macrophages are the most abundant and diverse subpopulation of leukocytes in VAT. Obesity induced significant transcriptional changes in all 15 leukocyte subpopulations, with many genes showing coordinated changes in expression across the leukocyte subpopulations. Additionally, obese VAT displayed expansion of one major macrophage subpopulation, which, in silico, was enriched in lipid binding and metabolic processes. This subpopulation returned from dominance in obesity to lean proportions after only 2 weeks of CR, although the pattern of gene expression overall remained similar. Surprisingly, CR VAT is dominated by a different macrophage subpopulation, which is absent in lean conditions. This subpopulation is enriched in genes related to phagocytosis and we postulate that its function includes clearance of dead cells, as well as excess lipids, contributing to limiting VAT inflammation and restoration of the homeostatic state.
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http://dx.doi.org/10.20900/immunometab20190008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687332PMC
July 2019

Defining Macrophages in the Heart One Cell at a Time.

Trends Immunol 2019 03 10;40(3):179-181. Epub 2019 Feb 10.

Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA. Electronic address:

Macrophages in the heart have dual roles in injury and repair after myocardial infarction, and understanding the two sides of this coin using traditional 'bulk cell' technologies has been challenging. By combining genetic fate-mapping and single-cell transcriptomics, a new study (Nat. Immunol. 2019;20:29-39) reveals how distinct macrophage populations expand and diverge across the healthy heart and after infarction.
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http://dx.doi.org/10.1016/j.it.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442674PMC
March 2019

Targeting inflammation in CVD: advances and challenges.

Authors:
Kathryn J Moore

Nat Rev Cardiol 2019 02;16(2):74-75

Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA.

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http://dx.doi.org/10.1038/s41569-018-0144-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392425PMC
February 2019

Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells.

Nat Commun 2018 11 27;9(1):5022. Epub 2018 Nov 27.

Division of Vascular Surgery, Department of Surgery, New York University Medical Center, New York, NY, 10016, USA.

Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) by vascular smooth muscle cells. Deficiency in MMP3 reduces ECM damage and the susceptibility of mice to develop AAA. Here, we establish netrin-1 as a major signal that mediates the dynamic crosstalk between inflammation and chronic erosion of the ECM in AAA.
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http://dx.doi.org/10.1038/s41467-018-07495-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258757PMC
November 2018

Macrophage Trafficking, Inflammatory Resolution, and Genomics in Atherosclerosis: JACC Macrophage in CVD Series (Part 2).

J Am Coll Cardiol 2018 10;72(18):2181-2197

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Atherosclerosis is characterized by the retention of modified lipoproteins in the arterial wall. These modified lipoproteins activate resident macrophages and the recruitment of monocyte-derived cells, which differentiate into mononuclear phagocytes that ingest the deposited lipoproteins to become "foam cells": a hallmark of this disease. In this Part 2 of a 4-part review series covering the macrophage in cardiovascular disease, we critically review the contributions and relevant pathobiology of monocytes, macrophages, and foam cells as relevant to atherosclerosis. We also review evidence that via various pathways, a failure of the resolution of inflammation is an additional key aspect of this disease process. Finally, we consider the likely role played by genomics and biological networks in controlling the macrophage phenotype in atherosclerosis. Collectively, these data provide substantial insights on the atherosclerotic process, while concurrently offering numerous molecular and genomic candidates that appear to hold great promise for selective targeting as clinical therapies.
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http://dx.doi.org/10.1016/j.jacc.2018.08.2147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522246PMC
October 2018

Molecular Pathways Underlying Cholesterol Homeostasis.

Nutrients 2018 06 13;10(6). Epub 2018 Jun 13.

Laboratorio de Lipides (LIM 10), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP 05403-000, Brazil.

Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern.
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http://dx.doi.org/10.3390/nu10060760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024674PMC
June 2018

Regulation of macrophage immunometabolism in atherosclerosis.

Nat Immunol 2018 06 18;19(6):526-537. Epub 2018 May 18.

Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA.

After activation, cells of the myeloid lineage undergo robust metabolic transitions, as well as discrete epigenetic changes, that can dictate both ongoing and future inflammatory responses. In atherosclerosis, in which macrophages play central roles in the initiation, growth, and ultimately rupture of arterial plaques, altered metabolism is a key feature that dictates macrophage function and subsequent disease progression. This Review explores how factors central to the plaque microenvironment (for example, altered cholesterol metabolism, oxidative stress, hypoxia, apoptotic and necrotic cells, and hyperglycemia) shape the metabolic rewiring of macrophages in atherosclerosis as well as how these metabolic shifts in turn alter macrophage immune-effector and tissue-reparative functions. Finally, this overview offers insight into the challenges and opportunities of harnessing metabolism to modulate aberrant macrophage responses in disease.
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http://dx.doi.org/10.1038/s41590-018-0113-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314674PMC
June 2018

Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis.

Circulation 2018 08;138(9):898-912

Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.).

Background: The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that antagonism of interleukin (IL)-1β reduces coronary heart disease in patients with a previous myocardial infarction and evidence of systemic inflammation, indicating that pathways required for IL-1β secretion increase cardiovascular risk. IL-1β and IL-18 are produced via the NLRP3 inflammasome in myeloid cells in response to cholesterol accumulation, but mechanisms linking NLRP3 inflammasome activation to atherogenesis are unclear. The cholesterol transporters ATP binding cassette A1 and G1 (ABCA1/G1) mediate cholesterol efflux to high-density lipoprotein, and Abca1/g1 deficiency in myeloid cells leads to cholesterol accumulation.

Methods: To interrogate mechanisms connecting inflammasome activation with atherogenesis, we used mice with myeloid Abca1/g1 deficiency and concomitant deficiency of the inflammasome components Nlrp3 or Caspase-1/11. Bone marrow from these mice was transplanted into Ldlr recipients, which were fed a Western-type diet.

Results: Myeloid Abca1/g1 deficiency increased plasma IL-18 levels in Ldlr mice and induced IL-1β and IL-18 secretion in splenocytes, which was reversed by Nlrp3 or Caspase-1/11 deficiency, indicating activation of the NLRP3 inflammasome. Nlrp3 or Caspase-1/11 deficiency decreased atherosclerotic lesion size in myeloid Abca1/g1-deficient Ldlr mice. Myeloid Abca1/g1 deficiency enhanced caspase-1 cleavage not only in splenic monocytes and macrophages, but also in neutrophils, and dramatically enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques, with reversal by Nlrp3 or Caspase-1/11 deficiency, suggesting that inflammasome activation promotes neutrophil recruitment and neutrophil extracellular trap formation in atherosclerotic plaques. These effects appeared to be indirectly mediated by systemic inflammation leading to activation and accumulation of neutrophils in plaques. Myeloid Abca1/g1 deficiency also activated the noncanonical inflammasome, causing increased susceptibility to lipopolysaccharide-induced mortality. Patients with Tangier disease, who carry loss-of-function mutations in ABCA1 and have increased myeloid cholesterol content, showed a marked increase in plasma IL-1β and IL-18 levels.

Conclusions: Cholesterol accumulation in myeloid cells activates the NLRP3 inflammasome, which enhances neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques. Patients with Tangier disease, who have increased myeloid cholesterol content, showed markers of inflammasome activation, suggesting human relevance.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160368PMC
August 2018

Long noncoding RNAs in lipid metabolism.

Curr Opin Lipidol 2018 06;29(3):224-232

Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA.

Purpose Of Review: Noncoding RNAs have emerged as important regulators of cellular and systemic lipid metabolism. In particular, the enigmatic class of long noncoding RNAs have been shown to play multifaceted roles in controlling transcriptional and posttranscriptional gene regulation. In this review, we discuss recent advances, current challenges and future opportunities in understanding the roles of lncRNAs in the regulation of lipid metabolism during health and disease.

Recent Findings: Despite comprising the majority of the transcriptionally active regions of the human genome, lncRNA functions remain poorly understood, with fewer than 1% of human lncRNAs functionally characterized. Broadly defined as nonprotein coding transcripts greater than 200 nucleotides in length, lncRNAs execute their functions by forming RNA-DNA, RNA-protein, and RNA-RNA interactions that regulate gene expression through diverse mechanisms, including epigenetic remodeling of chromatin, transcriptional activation or repression, posttranscriptional regulation of mRNA, and modulation of protein activity. It is now recognized that in lipid metabolism, just as in other areas of biology, lncRNAs operate to regulate the expression of individual genes and gene networks at multiple different levels.

Summary: The complexity revealed by recent studies showing how lncRNAs can alter systemic and cell-type-specific cholesterol and triglyceride metabolism make it clear that we have entered a new frontier for discovery that is both daunting and exciting.
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http://dx.doi.org/10.1097/MOL.0000000000000503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077844PMC
June 2018

Long non-coding RNAs regulating macrophage functions in homeostasis and disease.

Vascul Pharmacol 2019 03 13;114:122-130. Epub 2018 Mar 13.

Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

Non-coding RNAs, once considered "genomic junk", are now known to play central roles in the dynamic control of transcriptional and post-transcriptional gene expression. Long non-coding RNAs (lncRNAs) are an expansive class of transcripts broadly described as greater than 200 nucleotides in length. While most lncRNAs are species-specific, their lack of conservation does not imbue a lack of function. LncRNAs have been found to regulate numerous diverse biological functions, including those central to macrophage differentiation and activation. Through their ability to form RNA-DNA, RNA-protein and RNA-RNA interactions, lncRNAs have been implicated in the regulation of myeloid lineage determination, and innate and adaptive immune functions, among others. In this review, we discuss recent advances, current challenges and future opportunities in understanding the roles of lncRNAs in macrophage functions in homeostasis and disease.
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http://dx.doi.org/10.1016/j.vph.2018.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136978PMC
March 2019

Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression.

J Clin Invest 2017 Aug 26;127(8):2904-2915. Epub 2017 Jun 26.

Departments of Medicine (Cardiology) and Cell Biology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, USA.

Atherosclerosis is a chronic inflammatory disease, and developing therapies to promote its regression is an important clinical goal. We previously established that atherosclerosis regression is characterized by an overall decrease in plaque macrophages and enrichment in markers of alternatively activated M2 macrophages. We have now investigated the origin and functional requirement for M2 macrophages in regression in normolipidemic mice that received transplants of atherosclerotic aortic segments. We compared plaque regression in WT normolipidemic recipients and those deficient in chemokine receptors necessary to recruit inflammatory Ly6Chi (Ccr2-/- or Cx3cr1-/-) or patrolling Ly6Clo (Ccr5-/-) monocytes. Atherosclerotic plaques transplanted into WT or Ccr5-/- recipients showed reduced macrophage content and increased M2 markers consistent with plaque regression, whereas plaques transplanted into Ccr2-/- or Cx3cr1-/- recipients lacked this regression signature. The requirement of recipient Ly6Chi monocyte recruitment was confirmed in cell trafficking studies. Fate-mapping and single-cell RNA sequencing studies also showed that M2-like macrophages were derived from newly recruited monocytes. Furthermore, we used recipient mice deficient in STAT6 to demonstrate a requirement for this critical component of M2 polarization in atherosclerosis regression. Collectively, these results suggest that continued recruitment of Ly6Chi inflammatory monocytes and their STAT6-dependent polarization to the M2 state are required for resolution of atherosclerotic inflammation and plaque regression.
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http://dx.doi.org/10.1172/JCI75005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531402PMC
August 2017
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