Publications by authors named "Tessa J Barrett"

37 Publications

Chronic stress primes innate immune responses in mice and humans.

Cell Rep 2021 Sep;36(10):109595

Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA; Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY, USA. Electronic address:

Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.
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http://dx.doi.org/10.1016/j.celrep.2021.109595DOI Listing
September 2021

Reshaping of the gastrointestinal microbiome alters atherosclerotic plaque inflammation resolution in mice.

Sci Rep 2021 Apr 26;11(1):8966. Epub 2021 Apr 26.

Center for the Prevention of Cardiovascular Disease, Department of Medicine, New York University School of Medicine, New York, USA.

Since alterations in the intestinal microbiota may induce systemic inflammation and polarization of macrophages to the M1 state, the microbiome role in atherosclerosis, an M1-driven disease, requires evaluation. We aimed to determine if antibiotic (Abx) induced alterations to the intestinal microbiota interferes with atherosclerotic plaque inflammation resolution after lipid-lowering in mice. Hyperlipidemic Apoe mice were fed a western diet to develop aortic atherosclerosis with aortas then transplanted into normolipidemic wild-type (WT) mice to model clinically aggressive lipid management and promote atherosclerosis inflammation resolution. Gut microbial composition pre and post-transplant was altered via an enteral antibiotic or not. Post aortic transplant, after Abx treatment, while plaque size did not differ, compared to Apoe mice, Abx WT recipient mice had a 32% reduction in CD68-expressing cells (p = 0.02) vs. a non-significant 12% reduction in Abx WT mice. A trend toward an M1 plaque CD68-expresing cell phenotype was noted in Abx mice. By 16S rRNA sequence analysis, the Abx mice had reduced alpha diversity and increased Firmicutes/Bacteroidetes relative abundance ratio with a correlation between gut Firmicutes abundance and plaque CD68-expressing cell content (p < 0.05). These results indicate that in a murine atherosclerotic plaque inflammation resolution model, antibiotic-induced microbiome perturbation may blunt the effectiveness of lipid-lowering to reduce the content of plaque inflammatory CD68-expressing cells.
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http://dx.doi.org/10.1038/s41598-021-88479-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076321PMC
April 2021

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice.

Commun Biol 2021 03 26;4(1):420. Epub 2021 Mar 26.

Department of Microbiology, NYU School of Medicine, New York, NY, USA.

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68 and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68 upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.
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http://dx.doi.org/10.1038/s42003-021-01925-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997930PMC
March 2021

CCL20 in psoriasis: A potential biomarker of disease severity, inflammation, and impaired vascular health.

J Am Acad Dermatol 2021 Apr 28;84(4):913-920. Epub 2020 Nov 28.

Center for the Prevention of Cardiovascular Disease, New York University School of Medicine, New York, New York; Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York; Division of Hematology, New York University School of Medicine, New York, New York; Division of Vascular Surgery, Department of Surgery, New York University School of Medicine, New York, New York.

Background: Psoriasis is associated with increased cardiovascular risk that is not captured by traditional proinflammatory biomarkers.

Objective: To investigate the relationship between Psoriasis Area and Severity Index, circulating proinflammatory biomarkers, and vascular health in psoriasis.

Methods: In patients with psoriasis and in age and sex-matched controls, 273 proteins were analyzed with the Proseek Multiplex Cardiovascular disease reagents kit and Inflammatory reagents kit (Olink Bioscience), whereas vascular endothelial inflammation and health were measured via direct transcriptomic analysis of brachial vein endothelial cells.

Results: In psoriasis, chemokine ligand 20 (CCL20), interleukin (IL) 6, and IL-17A were the top 3 circulating proinflammatory cytokines. Vascular endothelial inflammation correlated with CCL20 (r = 0.55; P < .001) and less so with IL-6 (r = 0.36; P = .04) and IL-17A (r = 0.29; P = .12). After adjustment for potential confounders, the association between CCL20 and vascular endothelial inflammation remained significant (β = 1.71; P = .02). In nested models, CCL20 added value (χ = 79.22; P < .001) to a model already incorporating the Psoriasis Area and Severity Index, Framingham risk, high-sensitivity C-reactive protein, Il-17A, and IL-6 (χ = 48.18; P < .001) in predicting vascular endothelial inflammation.

Limitations: Our study was observational and did not allow for causal inference in the relationship between CCL20 and cardiovascular risk.

Conclusion: We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis.
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http://dx.doi.org/10.1016/j.jaad.2020.10.094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049184PMC
April 2021

β-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice.

J Lipid Res 2020 11 22;61(11):1491-1503. Epub 2020 Sep 22.

Department of Food Science and Human Nutrition, University of Illinois Urbana Champaign, Urbana, IL, USA

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of CVDs, and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affects atherosclerosis progression in the atheroprone LDLR-deficient mice. Compared with control-fed mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in / mice despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.
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http://dx.doi.org/10.1194/jlr.RA120001066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604725PMC
November 2020

Platelet and Vascular Biomarkers Associate With Thrombosis and Death in Coronavirus Disease.

Circ Res 2020 09 6;127(7):945-947. Epub 2020 Aug 6.

Department of Medicine (T.J.B., A.H.L., Y.X., J.H., J.S.B.), New York University Grossman School of Medicine, NY.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478197PMC
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

RAGE impairs murine diabetic atherosclerosis regression and implicates IRF7 in macrophage inflammation and cholesterol metabolism.

JCI Insight 2020 07 9;5(13). Epub 2020 Jul 9.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.

Despite advances in lipid-lowering therapies, people with diabetes continue to experience more limited cardiovascular benefits. In diabetes, hyperglycemia sustains inflammation and preempts vascular repair. We tested the hypothesis that the receptor for advanced glycation end-products (RAGE) contributes to these maladaptive processes. We report that transplantation of aortic arches from diabetic, Western diet-fed Ldlr-/- mice into diabetic Ager-/- (Ager, the gene encoding RAGE) versus WT diabetic recipient mice accelerated regression of atherosclerosis. RNA-sequencing experiments traced RAGE-dependent mechanisms principally to the recipient macrophages and linked RAGE to interferon signaling. Specifically, deletion of Ager in the regressing diabetic plaques downregulated interferon regulatory factor 7 (Irf7) in macrophages. Immunohistochemistry studies colocalized IRF7 and macrophages in both murine and human atherosclerotic plaques. In bone marrow-derived macrophages (BMDMs), RAGE ligands upregulated expression of Irf7, and in BMDMs immersed in a cholesterol-rich environment, knockdown of Irf7 triggered a switch from pro- to antiinflammatory gene expression and regulated a host of genes linked to cholesterol efflux and homeostasis. Collectively, this work adds a new dimension to the immunometabolic sphere of perturbations that impair regression of established diabetic atherosclerosis and suggests that targeting RAGE and IRF7 may facilitate vascular repair in diabetes.
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http://dx.doi.org/10.1172/jci.insight.137289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406264PMC
July 2020

Characterization of PCSK9 in the Blood and Skin of Psoriasis.

J Invest Dermatol 2021 02 29;141(2):308-315. Epub 2020 Jun 29.

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address:

Mechanisms explaining the link between psoriasis, a proinflammatory condition, and cardiovascular disease are not fully known. PCSK9 is predominantly expressed in hepatocytes as a critical regulator of lipid metabolism, and clinical trials targeting PCSK9 reduce cardiovascular disease. Independent of its role in lipid metabolism, PCSK9 levels associate with endothelial dysfunction and predict cardiovascular events. We used two separate human psoriasis cohorts and the K14-Rac1V12 murine model of psoriasis to investigate PCSK9 and cardiovascular risk in psoriasis. In both psoriasis cohorts (n = 88 and n = 20), PCSK9 levels were 20% and 13% higher than in age-, sex-, and cholesterol-matched controls, respectively (P < 0.05 for each comparison) and correlated with PASI (r = 0.43, P < 0.05). Despite no difference in hepatocyte expression, K14-Rac1V12 mice demonstrated skin-specific PCSK9 staining, which was confirmed in human psoriatic lesional skin. In patients with psoriasis, PCSK9 levels correlated with impaired endothelial vascular health (e.g., early atherosclerosis, β = 4.5, P < 0.01) and log converted coronary artery calcium score (β = 0.30, P = 0.01), which remained significant after adjustment for Framingham risk, body mass index, and active biologic use. Taken together, these findings suggest, independent of cholesterol, an association between circulating PCSK9 and early as well as advanced stages of atherosclerosis in psoriasis.
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http://dx.doi.org/10.1016/j.jid.2020.05.115DOI Listing
February 2021

Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis.

Circ Res 2020 09 22;127(7):877-892. Epub 2020 Jun 22.

Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia (A.J.M.).

Rationale: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear.

Objective: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis.

Methods And Results: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C subset, and neutrophils. Hematopoietic-restricted deletion of , , or its cognate receptor prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis.

Conclusions: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486277PMC
September 2020

Antisense oligonucleotide targeting of thrombopoietin represents a novel platelet depletion method to assess the immunomodulatory role of platelets.

J Thromb Haemost 2020 07 6;18(7):1773-1782. Epub 2020 May 6.

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

Background: Platelets are effector cells of the innate and adaptive immune system; however, understanding their role during inflammation-driven pathologies can be challenging due to several drawbacks associated with current platelet depletion methods. The generation of antisense oligonucleotides (ASOs) directed to thrombopoietin (Tpo) mRNA represents a novel method to reduce circulating platelet count.

Objective: To understand if Tpo-targeted ASO treatment represents a viable strategy to specifically reduce platelet count in mice.

Methods: Female and male mice were treated with TPO-targeted ASOs and platelet count and function was assessed, in addition to circulating blood cell counts and hematopoietic stem and progenitor cells. The utility of the platelet-depletion strategy was assessed in a murine model of lower airway dysbiosis.

Results And Conclusions: Herein, we describe how in mice, ASO-mediated silencing of hepatic TPO expression reduces platelet, megakaryocyte, and megakaryocyte progenitor count, without altering platelet activity. TPO ASO-mediated platelet depletion can be achieved acutely and sustained chronically in the absence of adverse bleeding. TPO ASO-mediated platelet depletion allows for the reintroduction of new platelets, an advantage over commonly used antibody-mediated depletion strategies. Using a murine model of lung inflammation, we demonstrate that platelet depletion, induced by either TPO ASO or anti-CD42b treatment, reduces the accumulation of inflammatory immune cells, including monocytes and macrophages, in the lung. Altogether, we characterize a new platelet depletion method that can be sustained chronically and allows for the reintroduction of new platelets highlighting the utility of the TPO ASO method to understand the role of platelets during chronic immune-driven pathologies.
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http://dx.doi.org/10.1111/jth.14808DOI Listing
July 2020

Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice.

JCI Insight 2020 04 9;5(7). Epub 2020 Apr 9.

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

Neutrophil extracellular traps (NETs) promote inflammation and atherosclerosis progression. NETs are increased in diabetes and impair the resolution of inflammation during wound healing. Atherosclerosis resolution, a process resembling wound healing, is also impaired in diabetes. Thus, we hypothesized that NETs impede atherosclerosis resolution in diabetes by increasing plaque inflammation. Indeed, transcriptomic profiling of plaque macrophages from NET+ and NET- areas in low-density lipoprotein receptor-deficient (Ldlr-/-) mice revealed inflammasome and glycolysis pathway upregulation, indicating a heightened inflammatory phenotype. We found that NETs declined during atherosclerosis resolution, which was induced by reducing hyperlipidemia in nondiabetic mice, but they persisted in diabetes, exacerbating macrophage inflammation and impairing resolution. In diabetic mice, deoxyribonuclease 1 treatment reduced plaque NET content and macrophage inflammation, promoting atherosclerosis resolution after lipid lowering. Given that humans with diabetes also exhibit impaired atherosclerosis resolution with lipid lowering, these data suggest that NETs contribute to the increased cardiovascular disease risk in this population and are a potential therapeutic target.
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http://dx.doi.org/10.1172/jci.insight.134796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205252PMC
April 2020

Activated Platelets Induce Endothelial Cell Inflammatory Response in Psoriasis via COX-1.

Arterioscler Thromb Vasc Biol 2020 05 5;40(5):1340-1351. Epub 2020 Mar 5.

From the Department of Medicine, Center for the Prevention of Cardiovascular Disease (M.S.G., E.A.F., J.S.B.), New York University School of Medicine.

Objective: Patients with psoriasis have impaired vascular health and increased cardiovascular disease (CVD). Platelets are key players in the pathogenesis of vascular dysfunction in cardiovascular disease and represent therapeutic targets in cardiovascular prevention. The object of this study was to define the platelet phenotype and effector cell properties on vascular health in psoriasis and evaluate whether aspirin modulates the platelet-induced phenotype. Approach and Results: Platelets from psoriasis patients (n=45) exhibited increased platelet activation (relative to age- and gender-matched controls, n=18), which correlated with psoriasis skin severity. Isolated platelets from psoriasis patients demonstrated a 2- to 3-fold (<0.01) increased adhesion to human aortic endothelial cells and induced proinflammatory transcriptional changes, including upregulation of (interleukin 8), , and Cox (cyclooxygenase)-2 Platelet RNA sequencing revealed an interferon signature and elevated expression of , which correlated with psoriasis disease severity (=0.83, =0.01). In a randomized trial of patients with psoriasis, 2 weeks of 81 mg low-dose aspirin, a COX-1 inhibitor, reduced serum thromboxane (Tx) B and reduced brachial vein endothelial proinflammatory transcript expression >70% compared with the no-treatment group (<0.01). Improvement in brachial vein endothelial cell inflammation significantly correlated with change in serum TxB (=0.48, =0.02).

Conclusions: In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation and suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03228017.
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http://dx.doi.org/10.1161/ATVBAHA.119.314008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180109PMC
May 2020

Macrophages in Atherosclerosis Regression.

Authors:
Tessa J Barrett

Arterioscler Thromb Vasc Biol 2020 01 14;40(1):20-33. Epub 2019 Nov 14.

From the Division of Cardiology, Department of Medicine, New York University.

Macrophages play a central role in the development of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary artery disease, peripheral artery disease, cerebrovascular disease, and aortic atherosclerosis. In each vascular bed, macrophages contribute to the maintenance of the local inflammatory response, propagate plaque development, and promote thrombosis. These central roles, coupled with their plasticity, makes macrophages attractive therapeutic targets in stemming the development of and stabilizing existing atherosclerosis. In the context of ASCVD, classically activated M1 macrophages initiate and sustain inflammation, and alternatively activated M2 macrophages resolve inflammation. However, this classification is now considered an oversimplification, and a greater understanding of plaque macrophage physiology in ASCVD is required to aid in the development of therapeutics to promote ASCVD regression. Reviewed herein are the macrophage phenotypes and molecular regulators characteristic of ASCVD regression, and the current murine models of ASCVD regression.
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http://dx.doi.org/10.1161/ATVBAHA.119.312802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946104PMC
January 2020

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

Apolipoprotein AI) Promotes Atherosclerosis Regression in Diabetic Mice by Suppressing Myelopoiesis and Plaque Inflammation.

Circulation 2019 10 30;140(14):1170-1184. Epub 2019 Sep 30.

Department of Medicine, Division of Cardiology (T.J.B., E.D., M.S.G., Y.O., E.A.F.), New York University School of Medicine.

Background: Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering.

Methods: Aortic arches containing plaques developed in mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined.

Results: Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus.

Conclusions: Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.039476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777860PMC
October 2019

Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo.

Arterioscler Thromb Vasc Biol 2019 10 22;39(10):1967-1985. Epub 2019 Aug 22.

From the Division of Endocrinology, Diabetes and Metabolism (H.R.C., D.S., N.G., Y.H., L.-A.H., S.S.C., J.G., S.B., I.J.G.), New York University School of Medicine, New York.

Objective: Fatty acid uptake and oxidation characterize the metabolism of alternatively activated macrophage polarization in vitro, but the in vivo biology is less clear. We assessed the roles of LpL (lipoprotein lipase)-mediated lipid uptake in macrophage polarization in vitro and in several important tissues in vivo. Approach and Results: We created mice with both global and myeloid-cell specific LpL deficiency. LpL deficiency in the presence of VLDL (very low-density lipoproteins) altered gene expression of bone marrow-derived macrophages and led to reduced lipid uptake but an increase in some anti- and some proinflammatory markers. However, LpL deficiency did not alter lipid accumulation or gene expression in circulating monocytes nor did it change the ratio of Ly6C/Ly6C. In adipose tissue, less macrophage lipid accumulation was found with global but not myeloid-specific LpL deficiency. Neither deletion affected the expression of inflammatory genes. Global LpL deficiency also reduced the numbers of elicited peritoneal macrophages. Finally, we assessed gene expression in macrophages from atherosclerotic lesions during regression; LpL deficiency did not affect the polarity of plaque macrophages.

Conclusions: The phenotypic changes observed in macrophages upon deletion of in vitro is not mimicked in tissue macrophages.
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http://dx.doi.org/10.1161/ATVBAHA.119.312389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761022PMC
October 2019

Monocytes and macrophages in atherogenesis.

Curr Opin Lipidol 2019 10;30(5):401-408

Division of Cardiology, Department of Medicine, New York University, New York, New York, USA.

Purpose Of Review: Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid cells concerning their metabolic and phenotypic function is increasingly appreciated. This review summarizes the recent monocyte and macrophage literature and highlights how differing subsets contribute to atherogenesis.

Recent Findings: Monocytes are short-lived cells generated in the bone marrow and released to circulation where they can produce inflammatory cytokines and, importantly, differentiate into long-lived macrophages. In the context of cardiovascular disease, a myriad of subtypes, exist with each differentially contributing to plaque development. Herein we describe recent novel characterizations of monocyte and macrophage subtypes and summarize the recent literature on mediators of myelopoiesis.

Summary: An increased understanding of monocyte and macrophage phenotype and their molecular regulators is likely to translate to the development of new therapeutic targets to either stem the growth of existing plaques or promote plaque stabilization.
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http://dx.doi.org/10.1097/MOL.0000000000000634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809604PMC
October 2019

HDL and Reverse Cholesterol Transport.

Circ Res 2019 05;124(10):1505-1518

Division of Cardiology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.).

Cardiovascular disease, with atherosclerosis as the major underlying factor, remains the leading cause of death worldwide. It is well established that cholesterol ester-enriched foam cells are the hallmark of atherosclerotic plaques. Multiple lines of evidence support that enhancing foam cell cholesterol efflux by HDL (high-density lipoprotein) particles, the first step of reverse cholesterol transport (RCT), is a promising antiatherogenic strategy. Yet, excitement towards the therapeutic potential of manipulating RCT for the treatment of cardiovascular disease has faded because of the lack of the association between cardiovascular disease risk and what was typically measured in intervention trials, namely HDL cholesterol, which has an inconsistent relationship to HDL function and RCT. In this review, we will summarize some of the potential reasons for this inconsistency, update the mechanisms of RCT, and highlight conditions in which impaired HDL function or RCT contributes to vascular disease. On balance, the evidence still argues for further research to better understand how HDL functionality contributes to RCT to develop prevention and treatment strategies to reduce the risk of cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.312617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813799PMC
May 2019

Inflammasome Signaling and Impaired Vascular Health in Psoriasis.

Arterioscler Thromb Vasc Biol 2019 04;39(4):787-798

From the Center for the Prevention of Cardiovascular Disease, Department of Medicine (M.S.G., E.A.F., J.S.B.), New York University School of Medicine, New York.

Objective- Psoriasis is an inflammatory skin disease which heightens the risk of cardiovascular disease. This study directly investigated vascular endothelial health and systemically altered pathways in psoriasis and matched controls. Approach and Results- Twenty patients (mean age, 40 years; 50% male) with active psoriasis and 10 age-, sex-matched controls were recruited. To investigate systemically alerted pathways, a deep sequencing omics approach was applied, including unbiased blood transcriptomic and targeted proteomic analysis. Vascular endothelial health was assessed by transcriptomic profiling of endothelial cells obtained from the brachial veins of recruited participants. Blood transcriptomic profiling identified inflammasome signaling as the highest differentially expressed canonical pathway ( Z score 1.6; P=1×10) including upregulation of CASP5 and interleukin ( IL) -1β. Proteomic panels revealed IL-6 as a top differentially expressed cytokine in psoriasis with pathway analysis highlighting IL-1β ( Z score 3.7; P=1.02×10) as an upstream activator of the observed upregulated proteins. Direct profiling of harvested brachial vein endothelial cells demonstrated inflammatory transcript (eg, IL-1β, CXCL10, VCAM-1, IL-8, CXCL1, Lymphotoxin beta, ICAM-1, COX-2, and CCL3) upregulation between psoriasis versus controls. A linear relationship was seen between differentially expressed endothelial inflammatory transcripts and psoriasis disease severity. IL-6 levels correlated with inflammatory endothelial cell transcripts and whole blood inflammasome-associated transcripts, including CASP5 and IL-1β. Conclusions- An unbiased sequencing approach demonstrated the inflammasome as the most differentially altered pathway in psoriasis versus controls. Inflammasome signaling correlated with psoriasis disease severity, circulating IL-6, and proinflammatory endothelial transcripts. These findings help better explain the heightened risk of cardiovascular disease in psoriasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03228017.
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http://dx.doi.org/10.1161/ATVBAHA.118.312246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436998PMC
April 2019

Circulating monocyte-platelet aggregates are a robust marker of platelet activity in cardiovascular disease.

Atherosclerosis 2019 03 2;282:11-18. Epub 2019 Jan 2.

Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA; Division of Vascular Surgery, Department of Surgery, New York University School of Medicine, New York, NY, USA; Division of Hematology, Department of Medicine, New York University School of Medicine, New York, NY, USA. Electronic address:

Background And Aims: Platelets are a major culprit in the pathogenesis of cardiovascular disease (CVD). Circulating monocyte-platelet aggregates (MPA) represent the crossroads between atherothrombosis and inflammation. However, there is little understanding of the platelets and monocytes that comprise MPA and the prevalence of MPA in different CVD phenotypes. We aimed to establish (1) the reproducibility of MPA over time in circulating blood samples from healthy controls, (2) the effect of aspirin, (3) the relationship between MPA and platelet activity and monocyte subtype, and (4) the association between MPA and CVD phenotype (coronary artery disease, peripheral artery disease [PAD], abdominal aortic aneurysm, and carotid artery stenosis).

Methods And Results: MPA were identified by CD14 monocytes positive for CD61 platelets in healthy subjects and in patients with CVD. We found that MPA did not significantly differ over time in healthy controls, nor altered by aspirin use. Compared with healthy controls, MPA were significantly higher in CVD (9.4% [8.2, 11.1] vs. 21.8% [11.5, 44.1], p < 0.001) which remained significant after multivariable adjustment (β = 9.1 [SER = 3.9], p = 0.02). We found PAD to be associated with a higher MPA in circulation (β = 19.3 [SER = 6.0], p = 0.001), and among PAD subjects, MPA was higher in subjects with critical limb ischemia (34.9% [21.9, 51.15] vs. 21.6% [15.1, 40.6], p = 0.0015), and significance remained following multivariable adjustment (β = 14.77 (SE = 4.35), p = 0.001).

Conclusions: Circulating MPA are a robust marker of platelet activity and monocyte inflammation, unaffected by low-dose aspirin, and are significantly elevated in subjects with CVD, particularly those with PAD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.12.029DOI Listing
March 2019

Whole-Blood Transcriptome Profiling Identifies Women With Myocardial Infarction With Nonobstructive Coronary Artery Disease.

Circ Genom Precis Med 2018 12;11(12):e002387

Leon H. Charney Division of Cardiology Department of Medicine, New York University School of Medicine (T.J.B., A.H.L., N.R.S., A.H., G.I.F., J.S.H., H.R.R., J.S.B.).

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http://dx.doi.org/10.1161/CIRCGEN.118.002387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455939PMC
December 2018

Diabetes-mediated myelopoiesis and the relationship to cardiovascular risk.

Ann N Y Acad Sci 2017 08;1402(1):31-42

Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York.

Diabetes is the greatest risk factor for the development of cardiovascular disease, which, in turn, is the most prevalent cause of mortality and morbidity in diabetics. These patients have elevations in inflammatory monocytes, a factor consistently reported to drive the development of atherosclerosis. In preclinical models of both type 1 and type 2 diabetes, studies have demonstrated that the increased production and activation of monocytes is driven by enhanced myelopoiesis, promoted by factors, including hyperglycemia, impaired cholesterol efflux, and inflammasome activation, that affect the proliferation of bone marrow precursor cells. This suggests that continued mechanistic investigations of the enhanced myelopoiesis and the generation of inflammatory monocytes are timely, from the dual perspectives of understanding more deeply the underlying bases of diabetes pathophysiology and identifying therapeutic targets to reduce cardiovascular risk in these patients.
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http://dx.doi.org/10.1111/nyas.13462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659728PMC
August 2017

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes.

J Clin Invest 2017 Jun 15;127(6):2133-2147. Epub 2017 May 15.

Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes.
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http://dx.doi.org/10.1172/JCI92450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451242PMC
June 2017

A wild-type mouse-based model for the regression of inflammation in atherosclerosis.

PLoS One 2017 14;12(3):e0173975. Epub 2017 Mar 14.

Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.

Atherosclerosis can be induced by the injection of a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (PCSK9)-encoding adeno-associated viral vector (AAVmPCSK9), avoiding the need for knockout mice models, such as low-density lipoprotein receptor deficient mice. As regression of atherosclerosis is a crucial therapeutic goal, we aimed to establish a regression model based on AAVmPCSK9, which will eliminate the need for germ-line genetic modifications. C57BL6/J mice were injected with AAVmPCSK9 and were fed with Western diet for 16 weeks, followed by reversal of hyperlipidemia by a diet switch to chow and treatment with a microsomal triglyceride transfer protein inhibitor (MTPi). Sixteen weeks following AAVmPCSK9 injection, mice had advanced atherosclerotic lesions in the aortic root. Surprisingly, diet switch to chow alone reversed hyperlipidemia to near normal levels, and the addition of MTPi completely normalized hyperlipidemia. A six week reversal of hyperlipidemia, either by diet switch alone or by diet switch and MTPi treatment, was accompanied by regression of atherosclerosis as defined by a significant decrease of macrophages in the atherosclerotic plaques, compared to baseline. Thus, we have established an atherosclerosis regression model that is independent of the genetic background.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173975PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349694PMC
September 2017

Activated Platelets Induce Endothelial Cell Activation via an Interleukin-1β Pathway in Systemic Lupus Erythematosus.

Arterioscler Thromb Vasc Biol 2017 04 2;37(4):707-716. Epub 2017 Feb 2.

From the Department of Medicine, Divisions of Cardiology (S.N., K.A.L., N.M.A., T.J.B., E.M., M.R., J.D.N., J.S.B.), Hematology (J.S.B.), and Rheumatology (R.C., J.N., S.R., J.P.B.), New York University School of Medicine, New York.

Objective: Systemic lupus erythematosus (SLE) is associated with the premature development of cardiovascular disease. The platelet-endothelium interaction is important in the pathogenesis of cardiovascular disease. In this study, we investigated the platelet phenotype from patients with SLE and matched controls, and their effect on endothelial cells.

Approach And Results: Platelet aggregability was measured in 54 SLE subjects off antiplatelet therapy (mean age 40.1±12.8 years; 82% female; 37% white) with age- and sex-matched controls. Platelets were coincubated with human umbilical vein endothelial cells (HUVECs) and changes to gene expression assessed by an RNA array and quantitative reverse transcription polymerase chain reaction. SLE disease activity index ranged from 0 to 22 (mean 5.1±3.9). Compared with controls, patients with SLE had significantly increased monocyte and leukocyte-platelet aggregation and platelet aggregation in response to submaximal agonist stimulation. An agnostic microarray of HUVECs cocultured with SLE platelets found a platelet-mediated effect on endothelial gene pathways involved in cell activation. Sera from SLE versus control subjects significantly increased (1) activation of control platelets; (2) platelet adhesion to HUVECs; (3) platelet-induced HUVEC gene expression of interleukin-8, and intercellular adhesion molecule 1; and (4) proinflammatory gene expression in HUVECs, mediated by interleukin-1β-dependent pathway. Incubation of SLE-activated platelets with an interleukin-1β-neutralizing antibody or HUVECs pretreated with interleukin-1 receptor antibodies attenuated the platelet-mediated activation of endothelial cells.

Conclusions: Platelet activity measurements and subsequent interleukin-1β-dependent activation of the endothelium are increased in subjects with SLE. Platelet-endothelial interactions may play a role in the pathogenesis of cardiovascular disease in patients with SLE.
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http://dx.doi.org/10.1161/ATVBAHA.116.308126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597960PMC
April 2017

Role of Myeloperoxidase Oxidants in the Modulation of Cellular Lysosomal Enzyme Function: A Contributing Factor to Macrophage Dysfunction in Atherosclerosis?

PLoS One 2016 20;11(12):e0168844. Epub 2016 Dec 20.

The Heart Research Institute, Sydney, New South Wales, Australia.

Low-density lipoprotein (LDL) is the major source of lipid within atherosclerotic lesions. Myeloperoxidase (MPO) is present in lesions and forms the reactive oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). These oxidants modify LDL and have been strongly linked with the development of atherosclerosis. In this study, we examined the effect of HOCl, HOSCN and LDL pre-treated with these oxidants on the function of lysosomal enzymes responsible for protein catabolism and lipid hydrolysis in murine macrophage-like J774A.1 cells. In each case, the cells were exposed to HOCl or HOSCN or LDL pre-treated with these oxidants. Lysosomal cathepsin (B, L and D) and acid lipase activities were quantified, with cathepsin and LAMP-1 protein levels determined by Western blotting. Exposure of J774A.1 cells to HOCl or HOSCN resulted in a significant decrease in the activity of the Cys-dependent cathepsins B and L, but not the Asp-dependent cathepsin D. Cathepsins B and L were also inhibited in macrophages exposed to HOSCN-modified, and to a lesser extent, HOCl-modified LDL. No change was seen in cathepsin D activity or the expression of the cathepsin proteins or lysosomal marker protein LAMP-1. The activity of lysosomal acid lipase was also decreased on treatment of macrophages with each modified LDL. Taken together, these results suggest that HOCl, HOSCN and LDL modified by these oxidants could contribute to lysosomal dysfunction and thus perturb the cellular processing of LDL, which could be important during the development of atherosclerosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168844PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173366PMC
June 2017

Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo.

Elife 2016 08 30;5. Epub 2016 Aug 30.

Division of Cardiology, NYU School of Medicine, New York, United States.

Apolipoprotein A1 (apoA1) is the major protein component of high-density lipoprotein (HDL) and has well documented anti-inflammatory properties. To better understand the cellular and molecular basis of the anti-inflammatory actions of apoA1, we explored the effect of acute human apoA1 exposure on the migratory capacity of monocyte-derived cells in vitro and in vivo. Acute (20-60 min) apoA1 treatment induced a substantial (50-90%) reduction in macrophage chemotaxis to a range of chemoattractants. This acute treatment was anti-inflammatory in vivo as shown by pre-treatment of monocytes prior to adoptive transfer into an on-going murine peritonitis model. We find that apoA1 rapidly disrupts membrane lipid rafts, and as a consequence, dampens the PI3K/Akt signalling pathway that coordinates reorganization of the actin cytoskeleton and cell migration. Our data strengthen the evidence base for therapeutic apoA1 infusions in situations where reduced monocyte recruitment to sites of inflammation could have beneficial outcomes.
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http://dx.doi.org/10.7554/eLife.15190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030090PMC
August 2016

Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages.

J Biol Chem 2016 May 29;291(21):11172-84. Epub 2016 Mar 29.

From the Department of Microbiology, New York University School of Medicine, New York, New York 10016,

Liver X receptors (LXR) are oxysterol-activated nuclear receptors that play a central role in reverse cholesterol transport through up-regulation of ATP-binding cassette transporters (ABCA1 and ABCG1) that mediate cellular cholesterol efflux. Mouse models of atherosclerosis exhibit reduced atherosclerosis and enhanced regression of established plaques upon LXR activation. However, the coregulatory factors that affect LXR-dependent gene activation in macrophages remain to be elucidated. To identify novel regulators of LXR that modulate its activity, we used affinity purification and mass spectrometry to analyze nuclear LXRα complexes and identified poly(ADP-ribose) polymerase-1 (PARP-1) as an LXR-associated factor. In fact, PARP-1 interacted with both LXRα and LXRβ. Both depletion of PARP-1 and inhibition of PARP-1 activity augmented LXR ligand-induced ABCA1 expression in the RAW 264.7 macrophage line and primary bone marrow-derived macrophages but did not affect LXR-dependent expression of other target genes, ABCG1 and SREBP-1c. Chromatin immunoprecipitation experiments confirmed PARP-1 recruitment at the LXR response element in the promoter of the ABCA1 gene. Further, we demonstrated that LXR is poly(ADP-ribosyl)ated by PARP-1, a potential mechanism by which PARP-1 influences LXR function. Importantly, the PARP inhibitor 3-aminobenzamide enhanced macrophage ABCA1-mediated cholesterol efflux to the lipid-poor apolipoprotein AI. These findings shed light on the important role of PARP-1 on LXR-regulated lipid homeostasis. Understanding the interplay between PARP-1 and LXR may provide insights into developing novel therapeutics for treating atherosclerosis.
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http://dx.doi.org/10.1074/jbc.M116.726729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900266PMC
May 2016
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